WO2022156240A1 - 一种血塞通分散片及其制备方法 - Google Patents

一种血塞通分散片及其制备方法 Download PDF

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WO2022156240A1
WO2022156240A1 PCT/CN2021/118216 CN2021118216W WO2022156240A1 WO 2022156240 A1 WO2022156240 A1 WO 2022156240A1 CN 2021118216 W CN2021118216 W CN 2021118216W WO 2022156240 A1 WO2022156240 A1 WO 2022156240A1
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weight
parts
dispersible tablet
xuesaitong
panax notoginseng
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PCT/CN2021/118216
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French (fr)
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许丹青
余国新
耿亮
朱亚东
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海南海力制药有限公司
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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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the invention relates to the technical field of traditional Chinese medicine, in particular to a Xuesaitong dispersible tablet and a preparation method thereof.
  • Panax notoginseng saponins In recent years, many pharmacological workers have conducted extensive research on the pharmacological effects of Panax notoginseng saponins, and studies have shown that it can protect ischemic brain injury, protect ischemic myocardial injury, improve arrhythmia, resist platelet aggregation, and resist thrombosis. It has a significant role in fighting liver fibrosis, protecting liver ischemia damage, improving immune function, etc., and its mechanism of action has been studied in detail and in-depth. The results show that Panax notoginseng saponins are non-specific calcium pump agonists. The study also confirmed that Panax notoginseng can correct the pathological state of myocardial energy imbalance.
  • Xuesaitong tablets and capsules are both traditional dosage forms, they have the disadvantages of slow dissolution and incomplete absorption in taking. Therefore, after research and development, more suitable Xuesaitong dispersible tablets have appeared, such as:
  • the Chinese invention patent with the authorization announcement number CN1164264C discloses a dispersible tablet of Panax notoginseng saponins and a preparation method thereof. Alcohol and cross-linked PVP, mix evenly; use 90% ethanol as a wetting agent to make soft material, granulate with 18-24 mesh sieve, and dry the wet granules at 50-80°C. Use a 18-24 mesh sieve to granulate, add magnesium stearate, mix evenly, and press to obtain a finished product.
  • the Chinese invention patent with application number CN202010563504.X discloses a Xuesaitong dispersible tablet and a preparation method thereof.
  • the preparation method is to weigh microcrystalline cellulose, crospovidone, croscarmellose sodium, low-substituted hypromellose, magnesium stearate, and silicon dioxide, then microcrystalline cellulose, crospovidone, croscarmellose sodium, low-substituted hypromellose, magnesium stearate, and dimethicone
  • the silicon oxide is mixed to obtain a mixture; the mixture is tabletted by a tablet machine to obtain Xuesaitong dispersible tablets.
  • the Chinese invention patent with the authorization announcement number CN1323667C discloses a kind of Panax notoginseng dispersible tablet, which has better disintegration effect and dissolution rate by internal and external addition of disintegrating agent through the secondary granulation method.
  • the Chinese invention patent with the authorization announcement number CN105055476B discloses a Xuesaitong dispersible tablet and a preparation method thereof. Homogeneous, use 50% ethanol to make soft material, granulate with a 16-mesh sieve, dry at 80 degrees Celsius, and then granulate with a 16-mesh sieve, add crospovidone and micropowder silica gel for addition, and press into tablets.
  • Xuesaitong dispersible tablets or Panax notoginseng dispersible tablets are made by using the total saponins of Panax notoginseng as raw materials, adding disintegrants, fillers, glidants, lubricants, etc.
  • This kind of dispersible tablet made by this kind of method has the following problems:
  • the purpose of the present invention is to provide a Xuesaitong dispersible tablet which can be rapidly disintegrated in an acidic environment, has a high degree of dissolution and high bioavailability, and provides a preparation method thereof.
  • the present invention provides a kind of Xuesaitong dispersible tablet, which is composed of total saponins of Panax notoginseng, calcium hydrogen phosphate, filler, disintegrant, glidant, lubricant and adhesive.
  • the dispersible tablet disintegrates within 60 seconds in a liquid environment with pH less than 5.5, 36 to 38 degrees, and the dissolution rate is greater than 99% in 120 seconds.
  • the filler is microcrystalline cellulose
  • Described disintegrating agent is carboxymethyl starch and cross-linked polyvinylpyrrolidone
  • Described glidant is magnesium stearate
  • the lubricant is micropowder silica gel
  • the binder is 95% ethanol.
  • each component distribution ratio is 20 parts by weight of Panax notoginseng saponins, 90-110 parts by weight of calcium hydrogen phosphate, 60-80 parts by weight of microcrystalline cellulose, 20-30 parts by weight of carboxymethyl starch, 10- 30 parts by weight of cross-linked polyvinylpyrrolidone, 1-10 parts by weight of magnesium stearate, 1-5 parts by weight of micropowder silica gel and 20-30 parts by weight of 95% ethanol.
  • the present invention also provides the preparation method of above-mentioned Xuesaitong dispersible tablet, comprising the following steps:
  • S3 adds sodium carbonate solution to pH 7 while stirring in the liquid phase of S2, and separates out precipitation simultaneously;
  • S5 adds carboxymethyl starch after micronizing the dry material and mixes it evenly;
  • S7 is granulated, add magnesium stearate, micropowder silica gel, cross-linked polyvinylpyrrolidone, mix well, and press into tablets to obtain Xuesaitong dispersible tablets.
  • micronized particle size in step S1 is 20-30 nanometers.
  • micronized particle size in step S5 is 40-60 nanometers.
  • the total saponins of Panax notoginseng have small micronized particle size and high bioavailability.
  • Fig. 1 is the process flow block diagram of Xuesaitong dispersible tablet of the present invention.
  • the invention provides a Xuesaitong dispersible tablet, which is composed of Panax notoginseng saponins, calcium hydrogen phosphate, a filler, a disintegrant, a glidant, a lubricant and a binder.
  • the Xuesaitong dispersible tablet has a pH lower than 5.5, 36 to 38 degrees liquid environment disintegrates within 60 seconds and the dissolution rate is greater than 99% in 120 seconds.
  • the above-mentioned filler is microcrystalline cellulose; the disintegrant is carboxymethyl starch and cross-linked polyvinylpyrrolidone; the glidant is magnesium stearate; the lubricant is micropowder silica gel; the adhesive 95% ethanol.
  • the proportion of each component is 20g of Panax notoginseng saponins, 90-110g of calcium hydrogen phosphate, 60-80g of microcrystalline cellulose, 20-30g of carboxymethyl starch, 10-30g of cross-linked polyvinylpyrrolidone, 1- 10g of magnesium stearate, 1-5g of micropowder silica gel and 20-30g of 95% ethanol are used to make one thousand dispersible tablets.
  • the preparation method of above-mentioned Xuesaitong dispersible tablet comprises the steps:
  • S1 micronizes the raw material of Panax notoginseng saponins of the recipe quantity to a particle size of 20-30 nanometers;
  • S3 adds sodium carbonate solution to pH 7 while stirring in the liquid phase of S2, and separates out precipitation simultaneously;
  • S5 is to add the carboxymethyl starch of the recipe quantity after the dry material is micronized and mix evenly, and the micronized particle size is 40-60 nanometers;
  • S7 is granulated, and the prescribed amounts of magnesium stearate, micropowder silica gel, and cross-linked polyvinylpyrrolidone are added, mixed, and pressed into tablets to obtain Xuesaitong dispersible tablets.
  • Panax notoginseng total saponins were micronized to an average particle size of 20 nanometers, added to 2000ml of water and 100g of calcium hydrogen phosphate was added simultaneously in a homogenizer, and 1mol/L hydrochloric acid was added to maintain pH6, and homogenize to no precipitation; After the liquid phase is introduced into the stirring dryer, the sodium carbonate solution is added to the liquid phase to adjust the pH to 7 and stirring at the same time to precipitate precipitation.
  • Dissolution test Use drug dissolution apparatus and high performance liquid chromatography to determine the main active components of three kinds of Panax notoginseng saponins in water at pH 5.5 and 37 degrees. The dissolution rate of 90 seconds and 120 seconds was tested ten times at each time point and the average value was obtained. The results are shown in Table 1.
  • Routine disintegration test Use a disintegration time limiter to measure whether the disintegration is completed within 3 minutes in 20°C + 1°C water, and whether it can pass the No. 2 sieve. The result is the average of three tests, see Table 2.
  • Disintegration test in acidic environment use a disintegration time limit tester to measure the disintegration time in pH 5.5, 37-degree water, whether it can pass the No. 2 sieve after complete disintegration, and the result is the average value of three tests, see Table 2.
  • the pH5.5, 37 degree liquid is used to simulate the acidic environment of the human stomach.
  • Panax notoginseng total saponins were micronized to an average particle size of 20 nanometers, added to 2000ml of water and 100g of calcium hydrogen phosphate was added simultaneously in a homogenizer, and 1mol/L hydrochloric acid was added to maintain pH6, and homogenize to no precipitation; After the liquid phase is introduced into the stirring dryer, the sodium carbonate solution is added to the liquid phase to adjust the pH to 7 and stirring at the same time to precipitate precipitation.
  • Disintegration and dissolution test methods are the same as in Example 1, and the results of the dissolution experiments are shown in Table 1, and the results of the disintegration experiments are shown in Table 2.
  • Example 1 Compared with Example 1, only the micronized average particle size of Panax notoginseng saponins is modified to 10 nanometers, and the rest are the same as Example 1.
  • Disintegration and dissolution test methods are the same as in Example 1, and the results of the dissolution experiments are shown in Table 1, and the results of the disintegration experiments are shown in Table 2.
  • Example 1 Compared with Example 1, this example only modifies the average particle size of the micronized dry material to 30 nanometers, and the rest are the same as Example 1.
  • Example 2 Take the dispersible tablet prepared in Example 1 provided by the Chinese invention patent with the authorization announcement number CN1164264C and carry out dissolution test and disintegration test. Disintegration and dissolution test methods are the same as in Example 1. The results are shown in Table 2.
  • Dissolution test and disintegration test were carried out with the dispersible tablet prepared in Example 1 provided by the Chinese invention patent with the authorization announcement number of CN105055476B, and the disintegration and dissolution test methods were the same as in Example 1. The results are shown in Table 2.
  • Example 1 The tablet obtained in Example 1 has a fast dissolution rate and an optimal dissolution rate, and all of Examples 1 to 3 can achieve good dissolution rate and dissolution rate;
  • Example 1 Compared with Comparative Example 1 and Comparative Example 2, Example 1 can be found that when the micronized particle size of the raw materials of Panax notoginseng saponins is too small, or the micronized particle size of the dry material is too small, the dissolution rate will be reduced, that is, particles will appear. Aggregation, and the minimum value of the micronized particle size, that is, the preparation method and conditions with the highest bioavailability, were tested by comparison.
  • Example 1 Compared with Comparative Examples 3 to 5, Example 1 can be found that, with respect to the Xuesaitong dispersible tablets in the prior art, the Xuesaitong dispersible tablets provided in the present invention can be rapidly dissolved in a short time and reach a good quality. dissolution rate.
  • embodiment 1 can be found that in comparative example 6, the micronized particle size of the same drug substance is 20 nanometers, but only calcium hydrogen phosphate is used as a filler, and the subsequent dry material is not micronized. In operation, the disintegration rate and dissolution rate are not ideal. Considering that when the raw material is micronized to a particle size of 20 nanometers, particle aggregation occurs during the dissolution process, resulting in insufficient dissolution rate.
  • Examples 1-3 and Comparative Examples 1-5 can all reach the requirements for dispersible tablets in the Chinese Pharmacopoeia, but in the case of simulating the acidic environment of the human stomach, the dispersible tablets provided by the present invention are compared with existing ones.
  • the existing technology can disintegrate faster, and can also pass through the No. 2 sieve after disintegration, that is, the disintegration effect meets the requirements.

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Abstract

一种血塞通分散片制备方法，将三七总皂苷原料微粉化后，加水和磷酸氢钙并加酸搅拌至无沉淀，之后加纯碱溶液调节pH至7并析出沉淀，将沉淀与液相共同搅拌干燥得干料，将干料再次微粉化后加入崩解剂混匀并用粘合剂制软材，软材制湿粒并干燥后，加入外加崩解剂、助流剂和润滑剂混合后整粒、压片即得。

Description

一种血塞通分散片及其制备方法 技术领域
本发明涉及中医药技术领域，具体涉及一种血塞通分散片及其制备方法。
背景技术
近年来，许多药理工作者对三七总皂苷的药理作用进行了广泛的研究，研究表明其在保护缺血性脑损伤、保护缺血性心肌损伤、改善心律失常、抗血小板聚集、抗血栓形成、对抗肝脏纤维化、保护肝脏缺血损伤、提高免疫机能等方面具有显著作用，并对其作用机理进行了详细而深入的研究，结果表明，三七总皂苷属于非特异性的钙泵激动剂，其研究还证实三七总苷可以纠正心肌能量失衡的病理状态，在降压和改善左心室舒张功能的同时，还可以明显的提高心肌细胞内肌浆网上钙泵的活性。云南省中医院内科，曾于1993年3至6月用三七总皂苷冲剂治疗老年性心脑血管疾病26例，均取得较满意的疗效。其中脑动脉硬化患者9例(含脑血栓形成两例)治疗后有8例之脑血流图恢复正常。
云南省人民医院寸淑芬等，于1994年10月至1995年2月间用三七总苷片治疗中医的眩晕、中风偏瘫及胸痹患者之表现旋转性眩晕、头痛、肢体麻木偏瘫、言语不利、胸痛等症状者50例，结果临床症状均有改善。其中20例眩晕病人治疗经头颅多普勒查有异常者11例(主要为供血不足)，治疗后复查，5例有不同程度的改善；另有胸痹患者10例，其中有心电图检查异常者6例(为心肌缺血，T波改变等)，治疗后4例有不同程度的改善。结论为有效率达75％至80％，且治疗过程中未发现任何不良反应。
由于血塞通片剂和胶囊均为传统剂型，在服用方面存在溶出缓慢，吸收不完全的缺点。因此经过研发已经出现了更符合需求的血塞通分散片例如：
授权公告号为CN1164264C的中国发明专利公开了一种三七总皂苷分散片及其制备方法，其制备方法是将原辅料分别过100目筛，按处方量称取三七总皂苷、乳糖、甘露醇和交联PVP，混合均匀；用90％的乙醇作润湿剂制软材，18～24目筛制粒，湿颗粒于50～80℃条件下进行干燥。用18～24目筛整粒，加入硬脂酸镁混匀用压片，即得成品。
申请号为CN202010563504.X的中国发明专利公开了一种血塞通分散片及其制备方法，其制备方法为分别称取微晶纤维素、交联聚维酮、交联羧甲纤维素钠、低取代羟丙纤维素、硬脂酸镁和二氧化硅，然后将微晶纤维素、交联聚维酮、交联羧甲纤维素钠、低取代羟丙纤维素、硬脂酸镁和二氧化硅进行混合，得到混合料；通过压片机对混合料进行压片，得到血塞通分散片。
授权公告号为CN1323667C的中国发明专利公开了一种三七分散片，其通过二次制粒法，将崩解剂进行内加和外加，具有更好的崩解效果和溶出度。
授权公告号为CN105055476B的中国发明专利公开了一种血塞通分散片及其制备方法，其制备方法为取三七总皂甙、微晶纤维素PH101和用于内加的交联聚维酮混合均匀，用50％乙醇制软材，16目筛制粒，80摄氏度烘干，再用16目筛整粒，加入用于外加的交联聚维酮和微粉硅胶均匀，压片，即得。
综上，目前血塞通分散片或者三七分散片，均是通过三七中的三七总皂苷作为原料，添加崩解剂、填充剂、助流剂、润滑剂等压片制成，但是这类方法制成的该类分散片具有如下问题：
1.由于三七总皂苷的微粉化程度会影响其溶出度，即微粉化的粒径越小其溶出度越高，但是当粒径小于一定值后随着比表面积增大，达到一定程度后自由能会自动减低，小粒子易聚集并影响药物溶出，而粒子大则会影响生物利用率。
2.由于制备原理大体相同，均是利用崩解剂外加、内加后通过水分使崩解剂膨胀进行崩解，且中国药典要求其在3分钟内崩解，因此现有技术中的血塞通分散片的崩解时间均较长。
发明内容
本发明的目的是提供一种于酸性环境下能够迅速崩解，且溶出度高，生物利用率高的血塞通分散片，并提供其制备方法。
为达到上述目的，本发明提供一种血塞通分散片，由三七总皂苷、磷酸氢钙、填充剂、崩解剂、助流剂、润滑剂和粘合剂构成，所述血塞通分散片于pH小于5.5、36至38度液体环境60秒内崩解且120秒溶出度大于99％。
其中，所述填充剂为微晶纤维素；
所述崩解剂为羧甲基淀粉和交联聚乙烯吡咯烷酮；
所述助流剂为硬脂酸镁；
所述润滑剂为微粉硅胶；
所述粘合剂为95％乙醇。
其中，上述各组分配比为20重量份的三七总皂苷、90-110重量份磷酸氢钙、60-80重量份的微晶纤维素、20-30重量份的羧甲基淀粉、10-30重量份的交联聚乙烯吡咯烷酮、1-10重量份的硬脂酸镁、1-5重量份的微粉硅胶以及20-30重量份的95％乙醇。
本发明还提供上述血塞通分散片的制备方法，包括如下步骤：
S1将三七总皂苷原料微粉化；
S2将微粉化的三七总皂苷加入水中并加入磷酸氢钙后于均质机中均质，均质过程中通过加入盐酸保持pH6-6.5，直至无沉淀；
S3向S2的液相中边搅拌边加入碳酸钠溶液至pH为7，同时析出沉淀；
S4将S3中的沉淀与液相于不高于70度环境下搅拌干燥至含水量小于10％得干料；
S5将干料微粉化后加入羧甲基淀粉混合均匀；
S6后加入95％的乙醇制软材,制粒，湿粒于大于75度条件干燥；
S7整粒，加入硬脂酸镁、微粉硅胶、交联聚乙烯吡咯烷酮混匀、压片即得血塞通分散片。
其中，步骤S1中微粉化粒径为20-30纳米。
其中，步骤S5中微粉化粒径为40-60纳米。
本发明提供的血塞通分散片的有益效果为：
1.其于pH小于5.5、36至38度液体环境60秒内崩解且120秒溶出度大于99％。
2.三七总皂苷微粉化粒径小，生物利用率高。
附图说明
下面结合附图和具体实施方式对本发明作进一步详细的说明。
图1是本发明的血塞通分散片的工艺流程方块图。
具体实施方式
下面结合本发明实施例中的附图，对本发明实施例中的技术方案进行清 楚、完整地描述。在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是本发明还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似推广，因此本发明不受下面公开的具体实施例的限制。
本发明提供一种血塞通分散片，由三七总皂苷、磷酸氢钙、填充剂、崩解剂、助流剂、润滑剂和粘合剂构成，所述血塞通分散片于pH小于5.5、36至38度液体环境60秒内崩解且120秒溶出度大于99％。
上述填充剂为微晶纤维素；所述崩解剂为羧甲基淀粉和交联聚乙烯吡咯烷酮；所述助流剂为硬脂酸镁；所述润滑剂为微粉硅胶；所述粘合剂为95％乙醇。
其各组分配比为20g的三七总皂苷、90-110g磷酸氢钙、60-80g的微晶纤维素、20-30g的羧甲基淀粉、10-30g的交联聚乙烯吡咯烷酮、1-10g的硬脂酸镁、1-5g的微粉硅胶以及20-30g的95％乙醇制一千片分散片。
上述血塞通分散片的制备方法，包括如下步骤：
S1将处方量的三七总皂苷原料微粉化至粒径20-30纳米；
S2将微粉化的三七总皂苷加入2000ml水中并加入处方量的磷酸氢钙后均质，均质过程中通过加入0.5mol/L盐酸保持pH6-6.5，直至无沉淀；
S3向S2的液相中边搅拌边加入碳酸钠溶液至pH为7，同时析出沉淀；
S4将S3中的沉淀与液相于不高于70度环境下搅拌干燥至含水量小于10％得干料；
S5将干料微粉化后加入处方量的羧甲基淀粉混合均匀，微粉化粒径40-60纳米；
S6后加入处方量的95％乙醇制软材,制粒，湿粒于大于75度条件下干燥；
S7整粒，加入处方量的硬脂酸镁、微粉硅胶、交联聚乙烯吡咯烷酮混匀、压片即得血塞通分散片。
实施例一
将20g三七总皂苷微粉化至平均粒径20纳米，加入2000ml水中并同时加入100g磷酸氢钙后于均质机中均质，通过加入1mol/L盐酸保持pH6,均质至无沉淀；将液相导入至搅拌干燥机后，再向液相中加入碳酸钠溶液调节pH为7并同时搅拌，析出沉淀，将搅拌干燥机升温至65度搅拌干燥至含水量10％后得干料，将干料取出进行微粉化至平均粒径40纳米后，向微粉化的干料中加入27.5g羧甲基淀粉混合均匀,向混合料中加入20g95％乙醇制软材，将软材过24目筛进行制粒，制得湿粒于80度环境烘干，用24目筛整粒，后加入20g交联聚乙烯吡咯烷酮、2g硬脂酸镁、0.6g微粉硅胶混匀、压片即得血塞通分散片。
溶出度测试：使用药物溶出仪、高效液相色谱，测定pH5.5、37度水中检测三种三七总皂苷的主要有效成分三七皂苷R 1、人参皂苷Rg 1、人参皂苷Rb 1分别于90秒、120秒溶出度，每一时间点做十次测试取均值，结果见表1。
常规崩解测试：使用崩解时限测定仪，在20℃+1℃水中测量3分钟内是否完成崩解，且能否通过2号筛，结果取三次测试平均值，见表2。
酸性环境崩解测试：使用崩解时限测定仪，于pH5.5、37度水中测定崩解时间，完全崩解后能否够通过2号筛，结果取三次测试平均值，见表2。
pH5.5、37度液体用于模拟人胃部酸性环境。
实施例二
将20g三七总皂苷微粉化至平均粒径20纳米，加入2000ml水中并同时加入100g磷酸氢钙后于均质机中均质，通过加入1mol/L盐酸保持pH6,均质至无沉淀；将液相导入至搅拌干燥机后，再向液相中加入碳酸钠溶液调节pH为7并同时搅拌，析出沉淀，将搅拌干燥机升温至65度搅拌干燥至含水量10％后得干料，将干料取出进行微粉化至平均粒径60纳米后，向微粉化的干料中加入27.5g羧甲基淀粉混合均匀,向混合料中加入20g95％乙醇制软材，将软材过24目筛进行制粒，制得湿粒于80度环境烘干，用24目筛整粒，后加入20g交联聚乙烯吡咯烷酮、2g硬脂酸镁、0.6g微粉硅胶混匀、压片即得血塞通分散片。
崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2。
实施例三
将20g三七总皂苷微粉化至平均粒径30纳米，加入2000ml水中并同时加入100g磷酸氢钙后于均质机中均质，通过加入1mol/L盐酸保持pH6,均质至无沉淀；将液相导入至搅拌干燥机后，再向液相中加入碳酸钠溶液调节pH为7并同时搅拌，析出沉淀，将搅拌干燥机升温至65度搅拌干燥至含水量10％后得干料，将干料取出进行微粉化至平均粒径40纳米后，向微粉化的干料中加入27.5g羧甲基淀粉混合均匀,向混合料中加入20g95％乙醇制软材，将软材过24目筛进行制粒，制得湿粒于80度环境烘干，用24目筛整粒，后加入20g交联聚乙烯吡咯烷酮、2g硬脂酸镁、0.6g微粉硅胶混匀、压片即得血塞通分散片。
崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2
对比例1
本实施例相较于实施例一仅将三七总皂苷微粉化平均粒径修改为10纳米，其余与实施例一均相同。
崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2
对比例2
本实施例相较于实施例一仅将干料微粉化平均粒径修改为30纳米，其余与实施例一均相同。
崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2。
对比例3
取授权公告号为CN1164264C的中国发明专利提供的实施例一制得的分散片进行溶出度测试和崩解测试，崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2。
对比例4
取授权公告号为CN1323667C的中国发明专利提供实施例三的方法制得的分散片进行溶出度测试和崩解测试，崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2。
对比例5
取授权公告号为CN105055476B的中国发明专利提供的实施例一制得的 分散片进行溶出度测试和崩解测试，崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2。
对比例6
将20g三七总皂苷微粉化至平均粒径20纳米，加入100g磷酸氢钙、27.5g羧甲基淀粉混合均匀,向混合料中加入20g95％乙醇制软材，将软材过24目筛进行制粒，制得湿粒于80度环境烘干，用24目筛整粒，后加入20g交联聚乙烯吡咯烷酮、2g硬脂酸镁、0.6g微粉硅胶混匀、压片即得，本对比例中仅仅将磷酸氢钙作为填充剂使用，崩解和溶出实验方法同实施例一，溶出实验结果见表1，崩解实验结果见表2。
表1：溶出度测试结果
Figure PCTCN2021118216-appb-000001
由表1可知：
1.实施例1得到的片剂其溶出速度快，溶出率最优，实施例1至3均能达到良好的溶出速度与溶出率；
2.实施例1与对比例1和对比例2相比能够发现，当三七总皂苷原料微粉化粒径过小，或者干料微粉化粒径过小时，会导致溶出度降低，即出现粒子聚集，并通过对比测试出微粉化粒径最小值，也即具有最高生物利用率的制备方法和条件。
3.实施例1与对比例3至5相比能够发现，相对于现有技术中的血塞通分散片，本发明中提供的血塞通分散片可在短时间内迅速溶出且达到很好的溶出度。
4.实施例1与对比例6相比能够发现，在对比例6中，同样采用原料药微粉化粒径为20纳米，但仅将磷酸氢钙作为填充剂使用，且后续干料无微粉化操作，其崩解速度与溶出率均不理想，考虑原料经微粉化至20纳米粒径时，溶出过程中出现粒子聚集，导致溶出度不足。
表2：崩解测试结果
Figure PCTCN2021118216-appb-000002
Figure PCTCN2021118216-appb-000003
由表2可知：实施例1-3以及对比例1-5均能达到中国药典中对分散片的要求，但在模拟人胃部酸性环境的情况下，本发明提供的分散片相较于现有技术能够更快的崩解，且崩解后同样能够通过2号筛，即崩解效果符合要求。
以上仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (7)

  1. 血塞通分散片，其特征在于，所述血塞通分散片由三七总皂苷、磷酸氢钙、填充剂、崩解剂、助流剂、润滑剂和粘合剂构成，所述血塞通分散片于pH小于5.5、36至38度液体环境60秒内崩解且120秒溶出度大于99％。
  2. 根据权利要求1所述的血塞通分散片，其特征在于，
    所述填充剂为微晶纤维素；
    所述崩解剂为羧甲基淀粉和交联聚乙烯吡咯烷酮；
    所述助流剂为硬脂酸镁；
    所述润滑剂为微粉硅胶；
    所述粘合剂为95％乙醇。
  3. 根据权利要求2所述的血塞通分散片，其特征在于，各组分配比为20重量份的三七总皂苷、90-110重量份磷酸氢钙、60-80重量份的微晶纤维素、20-30重量份的羧甲基淀粉、10-30重量份的交联聚乙烯吡咯烷酮、1-10重量份的硬脂酸镁、1-5重量份的微粉硅胶以及20-30重量份的95％乙醇。
  4. 如权利要求1至3任一所述的血塞通分散片的制备方法，其特征在于，包括如下步骤：
    S1将三七总皂苷原料微粉化；
    S2将微粉化的三七总皂苷加入水中并加入磷酸氢钙后于均质机中均质，均质过程中通过加入盐酸保持pH6-6.5，直至无沉淀；
    S3向S2的液相中边搅拌边加入碳酸钠溶液至pH为7，同时析出沉淀；
    S4将S3中的沉淀与液相于不高于70度环境下搅拌干燥至含水量小于10％得干料；
    S5将干料微粉化后加入羧甲基淀粉混合均匀；
    S6后加入95％的乙醇制软材,制粒，湿粒于大于75度条件干燥；
    S7整粒，加入硬脂酸镁、微粉硅胶、交联聚乙烯吡咯烷酮混匀、压片即得血塞通分散片。
  5. 根据权利要求4所述的血塞通分散片的制备方法，其特征在于，各组分用量为：20重量份的三七总皂苷、90-110重量份磷酸氢钙、60-80重量份的微晶纤维素、20-30重量份的羧甲基淀粉、10-30重量份的交联聚乙烯吡咯烷酮、1-10重量份的硬脂酸镁、1-5重量份的微粉硅胶以及20-30重量份的95％乙醇。
  6. 根据权利要求5所述的血塞通分散片的制备方法，其特征在于，步骤S1中微粉化粒径为20-30纳米。
  7. 根据权利要求6所述的血塞通分散片的制备方法，其特征在于，步骤S5中微粉化粒径为40-60纳米。
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