WO2021078087A1 - 靶向定位释放的中药丸剂及其制备方法 - Google Patents

靶向定位释放的中药丸剂及其制备方法 Download PDF

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WO2021078087A1
WO2021078087A1 PCT/CN2020/121803 CN2020121803W WO2021078087A1 WO 2021078087 A1 WO2021078087 A1 WO 2021078087A1 CN 2020121803 W CN2020121803 W CN 2020121803W WO 2021078087 A1 WO2021078087 A1 WO 2021078087A1
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pill
powder
layer
chinese medicine
powder layer
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French (fr)
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王丽
郭桂秋
董肖红
王爱云
翟勇
焦玉金
王媛媛
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荣昌制药(淄博)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
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/233—Bupleurum
    • 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
    • A61K36/284—Atractylodes
    • 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
    • A61K36/285—Aucklandia
    • 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
    • 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
    • A61K36/484—Glycyrrhiza (licorice)
    • 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
    • A61K36/532—Agastache, e.g. giant hyssop
    • 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)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • 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)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/89—Cyperaceae (Sedge family)
    • A61K36/8905—Cyperus (flatsedge)
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    • 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)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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

Definitions

  • the invention belongs to the technical field of medicine preparation, and specifically relates to a Chinese medicine pill with targeted and localized release and a preparation method thereof.
  • Shuganhewei Pills can significantly promote gastric emptying, inhibit gastric acid secretion, speed up the intestinal movement of rabbits in vivo, promote small intestine advancement, and relieve pain caused by thermal and chemical stimulation.
  • Shugan and Wei Pills are mainly Dami Pills or Shui Mi Pills.
  • This type of dosage form has certain shortcomings in clinical use.
  • the pills are large in size and difficult for patients to swallow. They often need to be chewed. They have poor taste and are difficult to swallow. Patients have poor compliance. .
  • Even though the water pill currently produced is small and has a diameter like mung bean, it is more convenient to take, but the preparation method is still conventional production, mainly using water as a binder, the powder is crushed and mixed evenly, pan pills or Use a machine to make pellets.
  • the Chinese medicine pill for targeted and localized release of the present invention includes a pill core layer, a middle powder layer and an outer coating powder layer, and the pill core layer is made of fried atractylodes, patchouli, raspberry and jiao betel nut
  • the middle powder layer is made of turmeric, tangerine peel and vinegar.
  • the outer coating powder layer is made of white peony, bergamot, black medicine, wood incense, licorice and Bupleurum; in each unit of preparation
  • the content of paeoniflorin is not less than 0.66mg, and the content of arecoline is not less than 0.07mg.
  • the mass ratio of the pellet core layer, the middle powder layer and the outer coating powder layer is 25-30:22-28:45-50.
  • the mass ratio of fried atractylodes macrocephala, patchouli, raspberry seed and jiao betel nut in the ball core layer is 4:2:3:3.
  • the mass ratio of turmeric, tangerine peel and vinegar aroma in the intermediate powder layer is 3:5:3.
  • the mass ratio of white peony, bergamot, black medicine, muxiang, licorice and Bupleurum in the outer coating powder layer is 3:10:3:3:1:1.
  • the method for preparing the Chinese medicine pill with targeted and localized release of the present invention includes the following steps:
  • Medicinal composition powder of intermediate powder layer turmeric, tangerine peel and vinegar odoriferous powder are selected according to the processing requirements, washed with water, and dried according to the weight ratio, and then pulverized into fine powder with an average particle size of 100 ⁇ m or less , To obtain the intermediate powder layer pharmaceutical composition powder;
  • the binder or wetting agent is a substance that has the function of wetting and bonding, preferably one or two of water or syrup.
  • the outer coating powder layer is composed of white peony root, bergamot, black medicine, wood incense, roasted licorice and Bupleurum.
  • the combination of these drugs has the effects of regulating qi and stomach, promoting qi and relieving pain.
  • Modern pharmacological research shows that the outer coating The paeoniflorin contained in the white peony powder in the powder layer has a strong anti-inflammatory and analgesic effect. After entering the stomach, it can quickly neutralize gastric acid and relieve pain, thereby achieving the purpose of treating the symptoms; the middle powder layer is composed of turmeric, tangerine peel and vinegar.
  • Figure 1 is a schematic diagram of the cross-sectional structure of a Chinese medicine pill for targeted and localized release of the present invention
  • FIG. 1 is the HPLC spectrum of paeoniflorin reference substance-1
  • Figure 5 is an HPLC chart of the sample of Example 1 Paeoniflorin dissolved in 20 minutes;
  • Figure 8 is an HPLC chart of the sample of Example 1 Paeoniflorin dissolved in 50 minutes;
  • FIG 10 is the HPLC spectrum of paeoniflorin reference substance-3
  • Figure 17 is a comparison diagram of the dissolution profile of paeoniflorin in Example 1 of the present invention.
  • Figure 18 is the HPLC spectrum of arecoline hydrobromide reference substance-1;
  • Figure 19 is the HPLC spectrum of arecoline hydrobromide reference substance-2;
  • Figure 20 shows the HPLC spectrum of the common product arecoline dissolved in 10 minutes
  • Figure 21 is the HPLC spectrum of the common product arecoline dissolved in 20 minutes
  • Figure 22 is an HPLC chart of the common product arecoline dissolved in 30 minutes
  • Figure 23 is the HPLC spectrum of the common product arecoline dissolved in 40 minutes
  • Figure 24 is the HPLC spectrum of the common product arecoline dissolved in 50 minutes
  • Figure 25 shows the HPLC spectrum of the common product arecoline dissolved in 60 minutes
  • Fig. 27 is an HPLC chart of the arecoline sample of Example 1 dissolved in 20 minutes;
  • Fig. 28 is an HPLC chart of the arecoline sample of Example 1 dissolved in 30 minutes;
  • Figure 29 is an HPLC chart of the arecoline sample of Example 1 dissolving for 40 minutes;
  • Figure 30 is an HPLC chart of the arecoline sample of Example 1 dissolving for 50 minutes;
  • Figure 31 is an HPLC chart of the arecoline sample of Example 1 dissolving for 60 minutes;
  • Figure 32 is a comparative diagram of the dissolution curves of arecoline in Example 1 of the present invention.
  • the targeted Chinese medicine pill includes a core layer 3, a middle powder layer 2 and an outer coating powder layer 1.
  • the core layer 3 is composed of fried atractylodes and patchouli.
  • the middle powder layer 2 is made of turmeric, tangerine peel and vinegar, and the outer coating powder layer 1 is made of white peony, bergamot, black medicine, wood incense, Made from licorice and Bupleurum.
  • the formula of the Chinese medicine pill is as follows:
  • Medicinal composition of middle powder layer turmeric 225g; tangerine peel 375g; vinegar incense 225g;
  • composition of the outer coating powder layer 225 g of white peony root; 750 g of bergamot; 225 g of black medicine; 225 g of woody; 75 g of licorice; 75 g of Bupleurum.
  • the above-mentioned formula pharmaceutical raw materials are made into pills according to the following preparation method, and the preparation method includes the following steps:
  • Pill core layer pharmaceutical composition powder stir fried atractylodes, patchouli, raspberry seeds and jiao betel nut according to the processing requirements, after cleaning, washing, drying, and mixing according to the weight ratio, and then crushing to an average particle size of 100 ⁇ m To obtain the powder of the drug composition of the pill core layer;
  • Intermediate powder layer medicinal composition powder turmeric, tangerine peel and vinegar odorant are cleaned, washed, and dried according to the processing requirements, and then mixed according to the weight ratio, and then pulverized into a fine powder with an average particle size of 100 ⁇ m. Obtain the intermediate powder layer pharmaceutical composition powder;
  • Outer coating powder layer medicinal composition powder the white peony root, bergamot, black medicine, woody, roasted licorice and Bupleurum are cleaned, washed, and dried according to the processing requirements, and then mixed according to the weight ratio, Then pulverize into a fine powder with an average particle diameter of 100 ⁇ m to obtain an outer coating powder layer pharmaceutical composition powder;
  • Determination method Take 7g of this product, according to the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Sibu General Rules 0931 Method 1), use 24mL of dilute hydrochloric acid and water to 1000mL as the dissolution medium, the speed is 100 revolutions per minute, the temperature is 37°C , Operate in accordance with the law. Take 5 mL of the solution and filter at 10, 20, 30, 40, 50, and 60 minutes, and take the subsequent filtrate as the test solution.
  • the drug release of the pill core layer is based on arecoline, as shown in Figure 18-31, the HPLC spectrum of the product of this example and the common product Shugan and Stomach Pills arecoline dissolved in 10-60 minutes, and the dissolution obtained according to the HPLC spectrum The degree data is shown in Table 1. As shown in Figure 32, the arecoline dissolution curves of the product of this example and the common product Shugan Hewei Pills are compared.

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Abstract

一种靶向定位释放的中药丸剂及其制备方法。所述中药丸剂包括丸芯层，中间粉层和外层包衣粉层，所述丸芯层由炒白术，广藿香，莱菔子和焦槟榔制成，所述中间粉层由郁金，陈皮和醋香附制成，所述外层包衣粉层由白芍，佛手，乌药，木香，炙甘草和柴胡制成；每单位制剂中芍药苷含量不少于0.66mg，槟榔碱含量不少于0.07mg。该药丸分为内，中，外三层，根据疾病的轻重缓急，通过不同药物分层定位释放发挥疗效，先治其标，后治其本，逐次发挥作用，最终达到标本兼治之目的，可显著提高临床疗效。

Description

靶向定位释放的中药丸剂及其制备方法 技术领域
本发明属于药物制备技术领域，具体涉及一种靶向定位释放的中药丸剂及其制备方法。
背景技术
中药治疗肝胃不和的药物比较常见，由于这类疾病属于慢性疾病，病因复杂，病程较长，常呈现持续性或反复发作状态。病人常出现两胁胀满，胃脘疼痛，食欲不振，呃逆呕吐，大便失调等消化不良症状。舒肝和胃丸是已上市药品，由醋香附、白芍、佛手、木香、郁金、炒白术、陈皮、柴胡、广藿香、炙甘草、莱菔子、焦槟榔、乌药等13味药组成的中药丸剂，临床上主要用于舒肝解郁，和胃止疼。对肝胃不和引起的上述症状有很好的治疗作用。
药效学研究表明，舒肝和胃丸能明显促进胃排空，抑制胃酸分泌，加快家兔在体肠运动及促进小肠推进，缓解热刺激和化学刺激所致疼痛等。
临床上舒肝和胃丸主要是大蜜丸或水蜜丸，该类剂型临床使用上存在一定缺陷，丸剂规格大，患者不易吞服，常需要咀嚼服用，口感差，难以下咽，病人依从性差。即使目前制作的水丸，丸粒小，径如绿豆，在服用上比较方便了，但制法仍然是常规制作，主要是以水等作粘合剂，将药粉进行粉碎后混合均匀，泛丸或用机器制成小丸。
这类丸剂崩解溶散速度慢，活性成分均匀溶出，不能定位释放，胃内滞留时间短，不能快速在病变炎症部位定位释药，从而造成活性成分流失，生物利用度低，影响药效作用的发挥，不能快速缓解胃部疼痛、促进排空。消除肝胃不舒的症状。
发明内容
本发明要解决的技术问题是：克服现有技术的不足，提供一种靶向定位释放的中药丸剂，通过药物分层定位释放发挥疗效，先治其标、后治其本，各层之间，逐次发挥作用，最终达到标本兼治之目的，显著提高临床疗效；同时本发明还提供其制备方法，制成多层丸剂，能够使不同成分在不同部位实现定位释放。
本发明所述的靶向定位释放的中药丸剂，包括丸芯层、中间粉层和外层包衣粉层，所述的丸芯层由炒白术、广藿香、莱菔子和焦槟榔制成，所述的中间粉层由郁金、陈皮和醋香附制成，所述的外层包衣粉层由白芍、佛手、乌药、木香、炙甘草和柴胡制成；每单位制剂中芍药苷含量不少于0.66mg，槟榔碱含量不少于0.07mg。
优选地，所述的丸芯层、中间粉层和外层包衣粉层的质量比为25-30:22-28:45-50。
优选地，所述的丸芯层中炒白术、广藿香、莱菔子和焦槟榔的质量比为4:2:3:3。
优选地，所述的中间粉层中郁金、陈皮和醋香附的质量比为3:5:3。
优选地，所述的外层包衣粉层中白芍、佛手、乌药、木香、炙甘草和柴胡的质量比为3:10:3:3:1:1。
本发明所述的靶向定位释放的中药丸剂的制备方法，包括以下步骤：
一、原料配制
(1)丸芯层药物组合物粉：将炒白术、广藿香、莱菔子和焦槟榔按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm以下的细粉，得到丸芯层药物组合物粉；
(2)中间粉层药物组合物粉：将郁金、陈皮和醋香附按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm以下的细粉，得到中间粉层药物组合物粉；
(3)外层包衣粉层药物组合物粉：将白芍、佛手、乌药、木香、炙甘草和柴胡按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm以下的细粉，得到外层包衣粉层药物组合物粉；
二、丸剂制作
(4)将丸芯层药物组合物粉与粘合剂或润湿剂置于混合机中混合成坨，然后用制丸机塑制成条，经切磋、滚圆成丸芯；
(5)将丸芯置于包衣锅中，依次用中间层药物组合物粉及外层药物组合物粉泛制成丸，经选丸、60-80℃干燥后即得。
所述的粘合剂或润湿剂为起润湿粘合作用的物质，优选水或糖浆中的一种或两种。
为更好的发挥药效，本发明对方中药味进行了分类，并在制丸过程中分层制作，以达到标本兼治的目的。
所制备的中药丸剂每单位丸剂的重量优选为0.045-0.0475g。
其中外层包衣粉层由白芍、佛手、乌药、木香、炙甘草和柴胡组成，诸药合用具有理气和胃、行气止痛之功效，通过现代药理研究表明，外层包衣粉层中白芍中所含芍药苷具有较强的抗炎止痛作用，进入胃部后，能迅速中和胃酸、缓解疼痛，从而达治标的目的；中间粉层由郁金、陈皮和醋香附组成，具有行气解郁、健脾和胃之功效，与外层包衣粉层具有协同作用，共同发挥制酸止痛之作用，共同达到治其标的目的；内层丸芯层由炒白术、广藿香、莱菔子和焦槟榔组成，能燥湿健脾、理气宽肠，对便溏泄泻具有良好的止泄泻，并可提高肠收缩幅度，促进小肠推动作用，对大便失调等症效果显著，对幽门螺旋杆菌有良好的抑制作用，能够彻底消灭致病之本，谓治其本。
体外释放对比研究：
所述丸剂外层的药物释放以芍药苷为指标，20分钟溶出不低于60％，40分钟溶出不低于80％，60分钟溶出不低于90％；丸剂丸芯层的药物释放以槟榔碱为指标，30分钟溶出应小于10％，60分钟溶出应小于70％。后续点不再检测，按溶出100％计算。
与现有技术相比，本发明的有益效果如下：
1、本发明根据药物组分性质不同，将其按照功能作用分类，分别粉碎，制成多层丸剂，使不同成分在不同部位实现定位释放，快速止疼、抑制胃酸分泌，并持续促进胃排空和肠道运动，达到舒肝解郁、和胃止痛的作用。
2、本发明方中诸药制丸分为内、中、外三层，根据疾病的轻重缓急，通过药物分层定位释放发挥疗效，先治其标、后治其本，各层之间，逐次发挥作用，最终达到标本兼治之目的，可显著提高临床疗效。
附图说明
图1为本发明靶向定位释放的中药丸剂的剖面结构示意图；
图2为芍药苷对照品-1的HPLC谱图；
图3为芍药苷对照品-2的HPLC谱图；
图4为实施例1样品芍药苷溶出10分钟的HPLC谱图；
图5为实施例1样品芍药苷溶出20分钟的HPLC谱图；
图6为实施例1样品芍药苷溶出30分钟的HPLC谱图；
图7为实施例1样品芍药苷溶出40分钟的HPLC谱图；
图8为实施例1样品芍药苷溶出50分钟的HPLC谱图；
图9为实施例1样品芍药苷溶出60分钟的HPLC谱图；
图10为芍药苷对照品-3的HPLC谱图；
图11为普通产品芍药苷溶出10分钟的HPLC谱图；
图12为普通产品芍药苷溶出20分钟的HPLC谱图；
图13为普通产品芍药苷溶出30分钟的HPLC谱图；
图14为普通产品芍药苷溶出40分钟的HPLC谱图；
图15为普通产品芍药苷溶出50分钟的HPLC谱图；
图16为普通产品芍药苷溶出60分钟的HPLC谱图；
图17为本发明实施例1中芍药苷溶出曲线对比图；
图18为氢溴酸槟榔碱对照品-1的HPLC谱图；
图19为氢溴酸槟榔碱对照品-2的HPLC谱图；
图20为普通产品槟榔碱溶出10分钟的HPLC谱图；
图21为普通产品槟榔碱溶出20分钟的HPLC谱图；
图22为普通产品槟榔碱溶出30分钟的HPLC谱图；
图23为普通产品槟榔碱溶出40分钟的HPLC谱图；
图24为普通产品槟榔碱溶出50分钟的HPLC谱图；
图25为普通产品槟榔碱溶出60分钟的HPLC谱图；
图26为实施例1样品槟榔碱溶出10分钟的HPLC谱图；
图27为实施例1样品槟榔碱溶出20分钟的HPLC谱图；
图28为实施例1样品槟榔碱溶出30分钟的HPLC谱图；
图29为实施例1样品槟榔碱溶出40分钟的HPLC谱图；
图30为实施例1样品槟榔碱溶出50分钟的HPLC谱图；
图31为实施例1样品槟榔碱溶出60分钟的HPLC谱图；
图32为本发明实施例1中槟榔碱溶出曲线对比图；
图中：1、外层包衣粉层；2、中间粉层；3、丸芯层。
具体实施方式
下面结合附图和实施例对本发明作进一步的说明。
实施例1
如图1所示，所述的靶向定位释放的中药丸剂，包括丸芯层3、中间粉层2和外层包衣粉层1，所述的丸芯层3由炒白术、广藿香、莱菔子和焦槟榔制成，所述的中间粉层2由郁金、陈皮和醋香附制成，所述的外层包衣粉层1由白芍、佛手、乌药、木香、炙甘草和柴胡制成。
所述中药丸剂的配方如下：
丸芯层药物组合物：炒白术300g；广藿香150g；莱菔子225g；焦槟榔225g；
中层粉层药物组合物：郁金225g；陈皮375g；醋香附225g；
外层包衣粉层组合物：白芍225g；佛手750g；乌药225g；木香225g；炙甘草75g；柴胡75g。
将上述配方药物原料按照以下制备方法制成丸剂，所述制备方法包括以下步骤：
一、原料配制
(1)丸芯层药物组合物粉：将炒白术、广藿香、莱菔子和焦槟榔按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm的细粉，得到丸芯层药物组合物粉；
(2)中间粉层药物组合物粉：将郁金、陈皮和醋香附按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm的细粉，得到中间粉层药物组合物粉；
(3)外层包衣粉层药物组合物粉：将白芍、佛手、乌药、木香、炙甘草和柴胡按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm的细粉，得到外层包衣粉层药物组合物粉；
二、丸剂制作
(4)称取720g丸芯层药物组合物粉加入360g纯化水置于槽型混合机中，混合15min制成药坨，然后用制丸机塑制成条，经切磋、滚圆成平均重量为0.5g/20粒的丸芯(湿丸)；
(5)将丸芯置于包衣锅中，称取中间粉层药物组合物粉660g，用纯化水作为粘合剂，泛丸，湿丸平均重量为0.96g/20粒；最后称取1280g外层包衣粉层药物组合物粉，用纯化水作为粘合剂，泛丸，湿丸平均重量为1.85g/20粒，选丸，70℃干燥后即得，丸重为0.90g/20粒。
体外溶出度检测
1、芍药苷的溶出度测定
测定方法：取本品7g，照溶出度与释放度测定法(中国药典2015年版四部通则0931第一法)，以稀盐酸24mL加水至1000mL为溶出介质，转速为每分钟100转，温度37℃，依法操作。分别于10、20、30、40、50、60分钟取溶液5mL滤过，取续滤液作为供试品溶液。另精密称取芍药苷对照品适量，加稀乙醇制成每1mL含16μg的溶液。以十八烷基硅烷键合硅胶为填充剂，以乙腈-0.05％磷酸二氢钾溶液(14:86)为流动相，流速：1.0mL/min，柱温：25℃，检测波长：230nm，理论塔板数按芍药苷计算不低于2000。精密吸取对照品溶液和供试品溶液10ul，注入液相色谱仪，测定，即得。
2、槟榔碱的溶出度测定
测定方法：取本品7g，照溶出度与释放度测定法(中国药典2015年版四部通则0931第一法)，以稀盐酸24mL加水至1000mL为溶出介质，转速为每分钟100转，温度37℃，依法操作。分别于10、20、30、40、50、60分钟取溶液5mL滤过，取续滤液作为供试品溶液。以十八烷基硅烷键合硅胶为填充剂，以0.15％三乙胺溶液(用磷酸调pH6.5)-甲醇(85:15)为流动相，流速：1.0mL/min，柱温：25℃，检测波长：215nm，理论塔板数按槟榔碱计算不低于2000。另取氢溴酸槟榔碱对照品适量，精密称定，加流动相制成每1mL含0.1mg的溶液，即得(槟榔碱重量＝氢溴酸槟榔碱/1.5214)。精密吸取对照品溶液和供试品溶液10ul，注入液相色谱仪，测定，即得。
3、测定结果
以市面销售的普通产品舒肝和胃丸作为对比，与实施例1制备的中药丸剂进行检测，所述丸剂外层的药物释放以芍药苷为指标，如图2-16为本实施例产品和普通产品舒肝和胃丸芍药苷溶出10-60分钟的HPLC谱图，根据HPLC谱图得到的溶出度数据见表1，如图17所示为本实施例产品和普通产品舒肝和胃丸的芍药苷溶出曲线对比图。
丸剂丸芯层的药物释放以槟榔碱为指标，如图18-31为本实施例产品和普通产品舒肝和胃丸槟榔碱溶出10-60分钟的HPLC谱图，根据HPLC谱图得到的溶出度数据见表1，如图32所示为本实施例产品和普通产品舒肝和胃丸的槟榔碱溶出曲线对比图。
表1芍药苷和槟榔碱溶出度
Figure PCTCN2020121803-appb-000001
当然，上述内容仅为本发明的较佳实施例，不能被认为用于限定对本发明的实施例范围。本发明也并不仅限于上述举例，本技术领域的普通技术人员在本发明的实质范围内所做出的均等变化与改进等，均应归属于本发明的专利涵盖范围内。

Claims (8)

  1. 一种靶向定位释放的中药丸剂，其特征在于：包括丸芯层、中间粉层和外层包衣粉层，所述的丸芯层由炒白术、广藿香、莱菔子和焦槟榔制成，所述的中间粉层由郁金、陈皮和醋香附制成，所述的外层包衣粉层由白芍、佛手、乌药、木香、炙甘草和柴胡制成；每单位制剂中芍药苷含量不少于0.66mg，槟榔碱含量不少于0.07mg。
  2. 根据权利要求1所述的靶向定位释放的中药丸剂，其特征在于：所述的丸芯层、中间粉层和外层包衣粉层的质量比为25-30:22-28:45-50。
  3. 根据权利要求1所述的靶向定位释放的中药丸剂，其特征在于：所述的丸芯层中炒白术、广藿香、莱菔子和焦槟榔的质量比为4:2:3:3。
  4. 根据权利要求1所述的靶向定位释放的中药丸剂，其特征在于：所述的中间粉层中郁金、陈皮和醋香附的质量比为3:5:3。
  5. 根据权利要求1所述的靶向定位释放的中药丸剂，其特征在于：所述的外层包衣粉层中白芍、佛手、乌药、木香、炙甘草和柴胡的质量比为3:10:3:3:1:1。
  6. 一种权利要求1-5任一所述的靶向定位释放的中药丸剂的制备方法，其特征在于：包括以下步骤：
    一、原料配制
    (1)丸芯层药物组合物粉：将炒白术、广藿香、莱菔子和焦槟榔按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm以下的细粉，得到丸芯层药物组合物粉；
    (2)中间粉层药物组合物粉：将郁金、陈皮和醋香附按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm以下的细粉，得到中间粉层药物组合物粉；
    (3)外层包衣粉层药物组合物粉：将白芍、佛手、乌药、木香、炙甘草和柴胡按照炮制要求进行净选、水洗、烘干处理后按照重量配比配料，然后粉碎成平均粒径100μm以下的细粉，得到外层包衣粉层药物组合物粉；
    二、丸剂制作
    (4)将丸芯层药物组合物粉与粘合剂或润湿剂置于混合机中混合成坨，然后用制丸机塑制成条，经切磋、滚圆成丸芯；
    (5)将丸芯置于包衣锅中，依次用中间层药物组合物粉及外层药物组合物粉泛制成丸，经选丸、干燥后即得。
  7. 根据权利要求6所述的靶向定位释放的中药丸剂的制备方法，其特征在于：所述的粘 合剂或润湿剂为水或糖浆中的一种或两种。
  8. 根据权利要求6所述的靶向定位释放的中药丸剂的制备方法，其特征在于：步骤(5)中所述的干燥温度为60-80℃。
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