WO2013177833A1

WO2013177833A1 - Dysmenorrhea-treating medicament and preparation method therefor

Info

Publication number: WO2013177833A1
Application number: PCT/CN2012/076880
Authority: WO
Inventors: 夏文; 安斯扬; 蒋坤; 吴春玲
Original assignee: 贵州百灵企业集团制药股份有限公司
Priority date: 2012-06-01
Filing date: 2012-06-14
Publication date: 2013-12-05
Also published as: CN103446238A

Abstract

A dysmenorrhea-treating medicament and a preparation method therefor. The medicament is prepared from scutellaria flavonoids aglycone, microcrystalline cellulose, a pregelatinized starch, a sodium carboxymethyl starch, a cross-linked povidone, dodecyl sodium sulfate, polysorbate 80, talcum powder, and povidone 30. The medicament is prepared into a dispersible tablet.

Description

说明书一种治疗痛经的药物及其制备方法领域 Description A medicament for treating dysmenorrhea and a preparation method thereof

本发明涉及一种治疗痛经的药物及其制备方法，属于药品技术的领域。背景技术 The invention relates to a medicine for treating dysmenorrhea and a preparation method thereof, and belongs to the field of medicine technology. Background technique

痛经是经期妇女临床常见病，多发病，特别是***少女约有半数以上的人受此痛苦。痛经多发生在***周期，而无***周期的子宫出血多无疼痛，这是由于***后在孕激素的作用下，分泌期的子宫粘膜能合成较多的***素 PGF₂。，其能剌激子宫肌肉收缩。痛经患者子宫***素 PGF_{2 a}含量增多，作用于子宫肌层和血管，引起强烈收缩产生疼痛。当***素 PGF_{2 a}进入血液循环后，还可以引起胃肠道平滑肌收缩，产生恶心、呕吐和腹泻诸症。随着子宫内膜的脱落，部分***素 PGF₂。也被靶细胞吸收或破坏，症状逐歩减轻至消失。我国每年约有 1000万少女进入***，痛经发病人数将达数千万。作为治疗手段，西医临床上通常采用阿托品、复方颠茄片等解痉药缓解症状，也可以用抗***素作用的药物如布洛芬、萘普生、消炎痛，以及酮洛芬、祛痛片等进行治疗。但以上药物对胃的剌激性大，且易产生耐药性及其他不良反应，很多患者由于耐受不了其副作用而不到有效的治疗。中药在治疔痛经方面有一定的优势，其中以温经化瘀者为多，如逐瘀温经汤，妇科通经丸、痛经宝、痛经灵冲剂、痛经丸等，这些药物的生产为解决广大患者疾苦，起到很好的作用。但以上药物服用量大，服用时间较长。 Dysmenorrhea is a common clinical disease in menstruating women, and it is a frequently-occurring disease. In particular, more than half of adolescent girls suffer from this problem. Dysmenorrhea often occurs in the ovulation cycle, while uterine bleeding without a ovulation cycle is more painless. This is because the uterine mucosa in the secretory phase can synthesize more prostaglandin PGF ₂ after ovulation. , it can stimulate the contraction of uterine muscles. In patients with dysmenorrhea, the content of prostaglandin PGF _{2 a is} increased, which acts on the myometrium and blood vessels of the uterus, causing intense contraction and pain. When prostaglandin PGF _{2 a} enters the blood circulation, it can also cause contraction of smooth muscles in the gastrointestinal tract, causing nausea, vomiting and diarrhea. With the detachment of the endometrium, part of the prostaglandin PGF ₂ . It is also absorbed or destroyed by the target cells, and the symptoms are gradually reduced to disappear. About 10 million girls enter puberty every year in China, and the number of dysmenorrhea will reach tens of millions. As a treatment, Western medicine usually uses atropine, compound belladonna tablets and other antispasmodic drugs to relieve symptoms, and anti-prostaglandin drugs such as ibuprofen, naproxen, indomethacin, and ketoprofen, sputum pain can also be used. Tablets and the like are treated. However, the above drugs are highly irritating to the stomach, and are prone to drug resistance and other adverse reactions. Many patients do not tolerate effective treatment because they cannot tolerate their side effects. Traditional Chinese medicine has certain advantages in the treatment of dysmenorrhea, among which there are many people with Wenjing Huayu, such as Zhuyu Wenjing Decoction, Gynecology Tongjing Pill, Dysmenorrhea, Tongjingling Granules, Dysmenorrhea Pills, etc. The majority of patients suffer and play a very good role. However, the above drugs are taken in large amounts and take longer.

因此，一种服用简便，安全高效且副作用小的治疗痛经的药物是患者迫切需要的。 Therefore, a drug that is simple, safe, and has a small side effect for treating dysmenorrhea is urgently needed by patients.

发明内容 Summary of the invention

本发明所要解决的技术问题在于，提供一种治疗痛经的药物及其制备方法。所述治疗痛经的药物具有清热祛湿、理血止痛的作用，产品质量稳定可控，服用简便、起效快，药效好，安全性高，副作用小，能有效治疗痛经。 The technical problem to be solved by the present invention is to provide a medicament for treating dysmenorrhea and a preparation method thereof. The medicine for treating dysmenorrhea has the functions of clearing away heat and dampness, regulating blood and relieving pain, and the product quality is stable and controllable, the taking is simple, the effect is fast, the medicine effect is good, the safety is high, the side effect is small, and the dysmenorrhea can be effectively treated.

为解决上述技术问题，本发明釆用如下技术方案实现：一种治疗痛经的药物，按照重量组份计算，由黄芩总黄酮苷元 150-170份、微晶纤维素 80-90份、预胶化淀粉 60-70份、羧甲基淀粉钠 15-25份、交联聚维酮 1-10份、十二烷基硫酸钠 0. 1-5份、聚山梨酯 80 0. 5-5份、滑石粉 3_5 份和聚维酮 K₃。 1-10份制成。 In order to solve the above technical problems, the present invention is implemented by the following technical solutions: A medicine for treating dysmenorrhea, according to the weight component, 150-170 parts of total flavonoid aglycone, 80-90 parts of microcrystalline cellulose, 60-70 parts of pregelatinized starch, sodium carboxymethyl starch 15-25 Parts, 1-10 parts of crospovidone, 0. 1-5 parts of sodium lauryl sulfate, 80. 5-5 parts of polysorbate, 3_5 parts of talc and povidone K ₃ . Made from 1-10 parts.

具体地，所述治疗痛经的药物按照重量组份计算，由黄芩总黄酮苷元 160 份、微晶纤维素 84份、预胶化淀粉 62. 48份、羧甲基淀粉钠 21份、交联聚维酮 7份、十二垸基硫酸钠 1. 75份、聚山梨酯 80 1. 2 份、滑石粉 4. 55份和聚维酮 Κ₃。 8份制成。 Specifically, the medicine for treating dysmenorrhea is calculated according to the weight component, 160 parts of total flavonoid aglycone of Astragalus, 84 parts of microcrystalline cellulose, 62.48 parts of pregelatinized starch, 21 parts of sodium carboxymethyl starch, cross-linking 7 parts of povidone, 1.75 parts of sodium dodecyl sulfate, 80 1. 2 parts of polysorbate, 4.55 parts of talc and vesicoside ₃ . Made in 8 parts.

所述药物的剂型为分散片。 The dosage form of the drug is a dispersible tablet.

所述分散片的制备方法为： The preparation method of the dispersible tablet is:

Α、称取十二垸基硫酸钠、聚山梨酯 80和聚维酮 Κ₃。配制成含聚维酮 Κ₃。为 5% 的水溶液，为 Α品； Strontium, sodium dodecyl sulfate, polysorbate 80 and povidone oxime _{3 were} weighed. Formulated to contain povidone oxime ₃ . a 5% aqueous solution, which is a defective product;

B、称取过 80-120目筛的黄芩总黄酮苷元，加微晶纤维素、预胶化淀粉和羧甲基淀粉钠，于混合制粒机中混合均匀，得 B品； B. Weigh the total flavonoid aglycone of Astragalus membranaceus with 80-120 mesh sieve, add microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and mix well in the mixing granulator to obtain B product;

C、将 A品和 B品混合，加入 B品 0. 03-1倍量的水搅拌，制粒，得颗粒，为 C. Mix product A and product B, add B product 0. 03-1 times the amount of water to stir, granulate, get granules,

C t¾ ; C t3⁄4 ;

D、取 C品于 60-80°C的温度下干燥 2-4小时，干燥后的颗粒用 20-40目筛整粒后，加入交联聚维酮及滑石粉过筛混合均勾，压片，即得。 D. Take C product and dry at 60-80 ° C for 2-4 hours. After drying the granules with 20-40 mesh sieve, add crospovidone and talcum powder and mix and sieve. Tablet, that is.

具体的，所述分散片的制备方法为： Specifically, the preparation method of the dispersible tablet is:

A、称取十二垸基硫酸钠、聚山梨酯 80和聚维酮 K₃。配制成含聚维酮 Κ₃。为 5% 的水溶液，为 Α品； A. Sodium dodecyl sulfate, polysorbate 80 and povidone K _{3 were} weighed. Formulated to contain povidone oxime ₃ . a 5% aqueous solution, which is a defective product;

B、称取过 100目筛的黄芩总黄酮苷元，加微晶纤维素、预胶化淀粉和羧甲基淀粉钠，于混合制粒机中混合均匀，得 B品； B. Weigh the total flavonoid aglycon of Astragalus membranaceus with 100 mesh sieve, add microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and mix well in a mixing granulator to obtain B product;

C、将 A品和 B品混合，加入 B品 0. 06倍量的蒸馏水搅拌，制粒，得颗粒，为 C π¾ C. Mix A and B, add B. 0. 06 times the amount of distilled water, stir, granulate, get granules, C π3⁄4

D、取 C品于 70°C的温度下干燥 3小时，干燥后的颗粒用 30目筛整粒后，加入交联聚维酮及滑石粉过筛混合均匀，调整片重为 0. 35g，压片，即得。 The granules are adjusted to a weight of 0.35 g, and the granules are added to the granules. The granules are added to the granules. Tableting, that is.

所制备的片剂每片含汉黄芩素 C₁₆H₁₂0₅不少于 17. 5mg。 ₅重量。 Each tablet containing the content of scutella C ₁₆ H ₁₂ 0 ₅ not less than 17. 5mg.

所述黄芩总黄酮苷元的制备方法为：取黄芩药材，粉碎为粗粉，加入 2-8 倍量煮沸后冷却至 25-45 °C的水，搅拌均匀，加盖密封，静置 12-36小时取出于 55-8CTC烘干，照流浸膏和浸膏剂项的渗漉法，加入 0. 2-2倍量乙醇，搅拌均匀，润湿装入渗漉筒，加入 2-8倍量乙醇密封浸泡，继续加至 4-20倍量的乙醇渗漉，渗漉液减压回收至相对密度为 1. 01-1. 04, 趁热加入 0. 5-3倍量冷水静置 4-18 小时，抽滤，粗结晶以适量水洗涤，于 55-8CTC烘干即得。 The preparation method of the total flavonoid aglycone of Astragalus membranaceus is as follows: taking the Astragalus membranaceus, pulverizing into a coarse powder, adding 2-8 Double boil, cool to 25-45 °C water, stir evenly, seal with lid, let stand for 12-36 hours, take out and dry at 55-8CTC, immersion method for extracting extract and extracting item, add 0 2-2 times the amount of ethanol, stir evenly, wet into the percolation tube, add 2-8 times the amount of ethanol sealed soaking, continue to add 4-20 times the amount of ethanol percolation, the percolate is reduced to relative recovery The density is 1. 01-1. 04, and the heat is added to 0. 5-3 times the amount of cold water is allowed to stand for 4-18 hours, suction filtration, coarse crystallization is washed with an appropriate amount of water, and dried at 55-8 CTC.

中医有关痛经的记载，最早见于《金匮要略》，其曰： "带下，经水不利，少腹满痛，经一月再见"。《诸病源候论》则首立 "月水来腹痛候"，认为 "妇人月水来腹痛者，由劳伤血气，以至体虛，受风冷之气客于胞络，损伤冲任之脉。 "，为研究痛经奠下了理论基础。后世医家为探索痛经的辩证规律做了进一步探索，《景岳全书.妇人规》曰： "凡妇人经行做痛，挟虚者多，全实者少，即如以可按拒按及经前经后辨虚实，固其大法也，然有气血本虛而血未得行者亦拒按，故于经前亦常有此症，此以气虛血滞无力流通而然"。 The records of traditional Chinese medicine related to dysmenorrhea are first seen in the "Golden Chambers", and the following: "Bottom, unfavorable by water, less abdominal pain, see you in January." "The Sources of Diseases" is the first to stand for "moon water to abdomen pain", and thinks that "women who come to the moon with pain in the moon, from the wounds of the blood, to the physical weakness, by the wind and cold gas in the cell, the damage is washed Pulse. ", laid the theoretical foundation for the study of dysmenorrhea. Later generations of doctors made further explorations to explore the dialectical law of dysmenorrhea. "Jing Yue Quanshu. Women's Regulations" 曰: "Where a woman is doing pain, there are many people who are guilty of guilty, and there are few people who are guilty. And before and after the menstruation to distinguish between the real and the real, the solid law is also fixed, but there are qi and blood deficiency and the blood has not been able to walk, but also often refused to pre-menstrual, so the qi deficiency and blood stasis is incapable of circulation."

黄芩是中国药典收载的常用中药之一，为唇形科植物黄芩 Scutel laria baicalensi s Georgi的干燥根。其味苦，性寒。归肺、胆、脾、大肠、小肠经，具有清热燥湿，泻火解毒，止血，安胎的功效，用于湿温、暑温胸闷呕恶，湿热痞满，泻痢，黄疸，肺热咳嗽，高热烦渴，血热吐衄，痈肿疮毒，胎动不安等。近代研究发现黄苓对子宫平滑肌收缩活动和对子宫***素生成有明显影响，单味黄芩制剂对原发性痛经有明显疗效。研究发现，黄芩中所含黄芩总黄酮苷元是治疗痛经的主要有效成分，本发明以黄芩总黄酮苷元为原料，与微晶纤维素等辅料制成的分散片，具有清热祛湿、理血止痛的作用，可用于原发性痛经湿热瘀阻证。症见：经前或经期小腹剌痛或胀痛拒按，有灼热感，或伴腰部胀痛，月经不调，血色黯红、质稠有块，带下量多，色黄质稠，或伴有低热起伏，舌质红，苔黄或腻，脉弦数或滑数。 Astragalus is one of the commonly used traditional Chinese medicines contained in the Chinese Pharmacopoeia. It is the dried root of the Scutel laria baicalensi s Georgi. Its bitter taste, cold. Back to lung, gallbladder, spleen, large intestine, small intestine, with heat and dampness, purging fire and detoxification, hemostasis, anti-fetal effect, for wet temperature, summer temperature, chest tightness, vomiting, dampness, diarrhea, jaundice, lung heat Cough, high fever, polydipsia, bloody vomiting, swollen sores, fetal movement and so on. Modern studies have found that Astragalus membranaceus has a significant effect on uterine smooth muscle contraction activity and uterine prostaglandin production. Single-flavored Astragalus preparation has obvious curative effect on primary dysmenorrhea. It has been found that the total flavonoid aglycone contained in Astragalus membranaceus is the main active ingredient for the treatment of dysmenorrhea. The present invention uses a total flavonoid aglycone of Astragalus membranaceus as a raw material, and a dispersible tablet made of excipients such as microcrystalline cellulose, which has heat, dampness and moisture. The role of blood pain relief can be used for primary dysmenorrhea dampness and heat stasis syndrome. Symptoms: Premenstrual or menstrual period abdominal pain or pain relief, have a burning sensation, or with waist pain, irregular menstruation, bloody blush, thick and thick, with a large amount, yellowish thick, or Accompanied by low heat fluctuations, red tongue, yellow or greasy moss, pulse number or slip number.

本发明鉴于黄芩生药中黄酮苷类的含量很高，其苷元的含量却很低，考虑到黄芩苷类属于葡萄糖醛类，难以用酸进行水解。为此，本发明通过黄芩自身酶的酶解作用，先将黄芩中大部分苷转化为苷元，再将酶解后黄芩用乙醇提取与精制，制备出含量达 56%以上的黄芩总黄酮苷元，分离出千层纸甲素、汉黄芩素和黄芩素三个有效成分。 The present invention has a high content of flavonoid glycosides in the crude drug of Astragalus membranaceus, and the content of aglycones is very low. Considering that baicalin is a glucosaldehyde, it is difficult to hydrolyze with an acid. Therefore, the present invention converts most of the glycosides of Astragalus membranaceus into aglycons by enzymatic hydrolysis of Astragalus sinensis, and then extracts and purifies the Astragalus membranaceus by ethanol after enzymatic hydrolysis to prepare total flavonoid glycosides of Astragalus membranaceus with a content of more than 56%. Yuan, separated from the three active ingredients of Melalin, Hanaxanthin and Baicalein.

以下是本发明所述药物工艺及临床研究结果实验例 1 : 辅料筛选试验 The following are the results of the pharmaceutical process and clinical research of the present invention. Experimental Example 1: Excipient screening test

1. 辅料性质、用量的调研 1. Investigation of the nature and dosage of excipients

由于剂型选择已确定采用分散片技术制备快崩速释型片剂，因此对制备分散片的主要辅料的特性及用量进行调研。 Since the dosage form selection has been determined to prepare a fast-breaking immediate release tablet using the dispersing tablet technique, the characteristics and amount of the main excipients for preparing the dispersion sheet were investigated.

1. 1辅料性质 1. 1 excipient properties

制备分散片的主要辅料有三种：优质崩解剂（吸水溶胀度〉5g/ml ); 溶胀辅料（遇水形成高粘度）；粘合剂最好采用有粘合作用又增加释放度的多功能辅料。 There are three main excipients for preparing dispersible tablets: high quality disintegrant (water swelling degree > 5g / ml); swelling auxiliary material (high viscosity formed by water); adhesive is preferably used with adhesive and increased release Excipients.

1. 1. 1优质崩解剂： 1. 1. 1 high quality disintegrant:

羧甲基淀粉钠 sodium carboxymethy starch (CMS- Na): 溶胀度 14. 8g/ml , 常用量 2-6%， 0. 5-8%，其特性是可作为片剂崩解剂及粘合剂。 Sodium carboxymethy starch (CMS- Na): swelling degree 14. 8g / ml, commonly used amount of 2-6%, 0. 5-8%, its characteristics can be used as a tablet disintegrating agent and adhesive .

交联聚维酮 crospovidon (交联 PVP， PVPP): 其性质是用作崩解剂，压成的片剂硬度大，外观光洁美观，崩解时限短，溶出速率高，且不会经时而变。具有较低的堆密度约 0. 26g/ml，易分布均匀，因吸水后不形成胶状溶液有利溶出。 Cross-linked povidone crospovidon (cross-linked PVP, PVPP): Its nature is used as a disintegrating agent, the tablet is compacted, the appearance is good, the disintegration time is short, the dissolution rate is high, and it does not change over time. . It has a low bulk density of about 0.26g/ml, and is easy to distribute evenly. It does not form a gelatinous solution after water absorption and is beneficial for dissolution.

低取代羟丙纤维素（L-HPC): 多用作崩解剂，并且有粘合作用。它的粗糙结构与颗粒之间有较大的镶嵌作用，使粘结强度增加，从而提高片剂的硬度和光泽度，对不易成型的药物可促进其成型，对崩解差的片剂可加速崩解，其作用是随取代基的增加而提高，取代百分比为 1%时，溶胀度为 500%, 取代百分比为 15% 时，溶胀度为 720%, 而淀粉的溶胀度只有 180%。一般用量 2-5%左右，堆密度 0. 44g/ml。 Low-substituted hydroxypropyl cellulose (L-HPC): Used as a disintegrant and has an adhesive effect. Its coarse structure and the particles have a large mosaic effect, which increases the bond strength, thereby increasing the hardness and gloss of the tablet, promoting the molding of the drug which is not easy to form, and accelerating the tablet with poor disintegration. Disintegration, its effect is increased with the increase of the substituent. When the percentage of substitution is 1%, the degree of swelling is 500%, when the percentage of substitution is 15%, the degree of swelling is 720%, and the degree of swelling of starch is only 180%. The general dosage is about 2-5%, and the bulk density is 0.44 g/ml.

由上可知， CMS-Na具有最大的溶胀度 a4. 8g/ml )，交联 PVP具有较低的堆密度（约 0. 26g/ml ) 易分布均匀，且吸水后不形成胶状溶液，有利溶出以及不会经时而变等特点，故以上两种辅料是本发明期望筛选的崩解剂。 From the above, CMS-Na has the largest degree of swelling a4. 8g / ml), cross-linked PVP has a low bulk density (about 0. 26g / ml), easy to distribute evenly, and does not form a colloidal solution after water absorption, which is advantageous The above two excipients are the disintegrating agents desired to be screened by the present invention because of the characteristics of dissolution and no change over time.

1. 1. 2溶胀辅料： 1. 1. 2 swelling auxiliary materials:

预胶化淀粉（可压性淀粉）：预胶化淀粉的特性是在受压变形同时有一定氢键结合，致使弹性复原率在受压形成实体的压力下，迅速下降，之后趋于平缓。预胶化淀粉有自身润滑性，流动性比淀粉、微晶纤维素好，国产品休止角为 36. 56° ，它具有粘合性，可增加片剂硬度，减少脆碎度，还能加速片剂的崩解和溶出，提高生物利用度，是新的直接压片辅料，具有粘合、崩解双重性能，在粉末直接压片不加粘合剂，无水份，加热等因素情况下药物溶出不受陈化时间的影响。用量 5-75°/。（稀释剂），堆密度（国产）： 0. 5-0. 6g/ml , 粒度分布：无大于 80目者，大于 120目占 5%， 95%通过 120目。 Pregelatinized starch (compressible starch): The characteristic of pregelatinized starch is that it has a certain hydrogen bonding at the same time of compression deformation, so that the elastic recovery rate rapidly drops under the pressure of the formed body under pressure, and then tends to be gentle. Pregelatinized starch has self-lubricating properties, and its fluidity is better than that of starch and microcrystalline cellulose. The angle of repose of the national product is 36.56°. It has adhesiveness, which can increase the hardness of the tablet, reduce the friability and accelerate. Disintegration and dissolution of tablets, improve bioavailability, is a new direct compression excipient, with dual properties of adhesion and disintegration, in the case of direct compression of the powder without adhesive, anhydrous parts, heating, etc. Drug dissolution is not affected by aging time influences. The dosage is 5-75 ° /. (Diluent), Bulk density (domestic): 0. 5-0. 6g/ml, particle size distribution: no more than 80 mesh, more than 120 mesh accounted for 5%, 95% passed 120 mesh.

维晶纤维素：棒状或颗粒状的晶体，其分子间存在氢键，受压时氢键締合，故具有高度的可压性，当水分子进入含有微晶纤维素片剂内部，氢键即刻断裂，因此可用作崩解剂，和预胶化淀粉一样在受压形成实体时弹性复原率迅速下降，趋于平稳，具有较好的塑性变形能力。休止角 51. 37° — 60. 32° 微晶纤维素摩擦系数很小，故压片时一般不需加润滑剂，但当药物或其他辅料的含量超过 20% 时就必须加润滑剂，微晶纤维素是一种多功能辅料，可以作填充，崩解，助流，粘合剂，用作填充剂用量约 10-30%， 15-45%。溶胀度 3. 4ml/_{g o} 处方中用量在 20%以上有较好的崩解作用。 Crystalline cellulose: rod-like or granular crystals with hydrogen bonds between molecules, hydrogen bonding under pressure, so they have a high degree of compressibility, when water molecules enter the interior of microcrystalline cellulose containing tablets, hydrogen bonds It is immediately broken, so it can be used as a disintegrating agent. As with pregelatinized starch, the elastic recovery rate rapidly decreases when it is pressed into a solid, tends to be stable, and has good plastic deformation ability. Angle of repose 51. 37° — 60. 32° Microcrystalline cellulose has a small coefficient of friction, so it is generally not necessary to add lubricant when compressing, but it must be added when the content of drugs or other excipients exceeds 20%. Crystalline cellulose is a multifunctional excipient that can be used as a filler, disintegration, flow aid, binder, and is used as a filler in an amount of about 10-30%, 15-45%. Swelling degree 3. 4ml / _{go in the} prescription of more than 20% has a good disintegration effect.

药用淀粉（玉米淀粉溶胀度 1. 3ml/g，马铃薯淀粉溶胀度 3. 4ml/g)_: 在水中加热至 68-72°C则糊化，用量一般为干颗粒重 20%以上，若用量多则难以干燥，特别是用流化床干燥法更为明显，压制的片剂硬度差，且有膨胀倾向，故一般少单独使用。堆密度 0. 57g/ml。 Medicinal starch (swelling degree of corn starch 1. 3ml / g, swelling degree of potato starch 3. 4ml / g) _: gelatinized when heated to 68-72 ° C in water, the amount is generally more than 20% by weight of dry granules, if the dosage In many cases, it is difficult to dry, especially in the fluidized bed drying method. The pressed tablets have poor hardness and tend to expand, so they are generally used less separately. The bulk density was 0.57 g/ml.

由上可知，可压性淀粉及微晶纤维素具有良好的可压性及成型性，与乳糖、淀粉等辅料比较，制出的片剂硬度最大，是本发明期望筛选的填充剂。 As can be seen from the above, the compressible starch and the microcrystalline cellulose have good compressibility and moldability, and the prepared tablet has the highest hardness as compared with the auxiliary materials such as lactose and starch, and is a filler which is desired to be screened by the present invention.

1. 1. 3粘合剂： 1. 1. 3 adhesive:

聚维酮 Palyvidoue (PVP) ： PVP为线型 N- 乙烯基 -2-吡咯垸酮的聚合物，它既易溶于水又能溶于一元醇如乙醇，多元醇如丙二醇等，因此在药剂上为常用的多功能粘合剂，具吸湿性，化学上呈惰性，无毒（大鼠口服 LD₅。M00g/kg)，对皮肤，粘膜无剌激，不产生过敏现象，对于疏水性药物以其水溶液作粘合剂，不但易于均匀湿润，还能使疏水性药物颗粒表面具有亲水性，增加药物的溶出度， PVP还可用于流化床喷雾干燥法制粒，常用 2-10%PVPK₃。溶液作粘合剂可制得质量高的颗粒。相同浓度的溶液其粘度与 PVP分子量成正比。一般采用 K值将分子量分级如表 1。 Polyvone Palyvidoue (PVP): PVP is a linear N-vinyl-2-pyrrolidone polymer which is soluble in water and soluble in monohydric alcohols such as ethanol, polyols such as propylene glycol, etc. It is a commonly used multifunctional adhesive, hygroscopic, chemically inert, non-toxic (rat oral LD ₅ .M00g/kg), no irritating to skin and mucous membranes, no allergic phenomenon, for hydrophobic drugs The aqueous solution is used as a binder, which not only is easy to uniformly wet, but also makes the surface of the hydrophobic drug particles hydrophilic and increases the dissolution rate of the drug. PVP can also be used for fluidized bed spray drying granulation, commonly used 2-10% PVPK ₃ . The solution acts as a binder to produce high quality granules. The viscosity of the same concentration of solution is proportional to the molecular weight of PVP. The molecular weight is generally classified by the K value as shown in Table 1.

PVP的 K值与分子量的关系见表 1 : The relationship between the K value of PVP and molecular weight is shown in Table 1:

表 1 Table 1

κ值 15 25 30 60 90 平均分子量 10000 25000 40000 160000 360000 分散片粘合剂大多采用 PVP和 HPMC (羟丙甲基纤维素）的稀醇溶液或水溶液，极少采用淀粉桨。 Κ15 25 30 60 90 Average molecular weight 10000 25000 40000 160000 360000 Most of the dispersible tablet adhesives use a dilute alcohol solution or an aqueous solution of PVP and HPMC (hydroxypropylmethylcellulose), and starch paste is rarely used.

羟丙基甲基纤维素 Hydroxypropyl Methylcel lulose ( HPMC): 在水中溶解形成澄明至乳白色具有粘性的胶状溶液，有部分型号的产品可溶于乙醇等有机溶剂。本品低粘度者作为片剂粘合剂和崩解剂，高粘度者仅作粘合剂，用量因型号和要求不同而异，一般为 2-5%。其特点崩解迅速，溶出速率高。 Hydroxypropylmethylcellulose Hydroxypropyl Methylcel lulose (HPMC): Dissolved in water to form a clear, creamy, viscous, colloidal solution. Some models are soluble in organic solvents such as ethanol. The low viscosity of this product is used as a tablet binder and disintegrant. The high viscosity is only used as a binder. The amount varies depending on the model and requirements, and is generally 2-5%. Its characteristics are rapid disintegration and high dissolution rate.

本发明为了考察 PVPK₃。的浓度，拟选择 3%低浓度进行初筛。因前面选择的微晶纤维素及预胶化淀粉都具粘合特性，而 HPMC粘度较大且规格不易掌握，故不宜选用。 The present invention is to investigate PVPK ₃ . The concentration, it is proposed to select 3% low concentration for primary screening. Since the microcrystalline cellulose and the pregelatinized starch selected in the foregoing have adhesive properties, the HPMC has a large viscosity and is difficult to grasp, so it is not suitable for use.

1. 1. 4表面活性剂： 1. 1. 4 surfactant:

是辅助崩解剂，主要是增加片剂的湿润性，一般疏水性或不溶性药物对水缺乏结合力，其孔隙中不易为水所透入，当加入适量表面活性剂能较好的解决。常用的表面活性剂有聚山梨酯 80，十二垸基硫酸钠等。表面活性剂对固体药物的湿润作用可提高药物溶出度。 It is an auxiliary disintegrating agent, mainly to increase the wettability of the tablet. Generally, the hydrophobic or insoluble drug has a lack of binding ability to water, and the pores are not easily penetrated by water, and the addition of an appropriate amount of the surfactant can be better solved. Commonly used surfactants are polysorbate 80, sodium dodecyl sulfate and the like. The wetting effect of the surfactant on the solid drug can increase the dissolution of the drug.

聚山梨酯 80: 适用于主药疏水性及水溶性差的药物或单用羧甲基淀粉钠而崩解改善不明显的药物，一般用量为 0. 2-0. 5%。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。.

十二垸基硫酸钠：为水溶性润滑剂，可代替单硬脂酸镁作润滑剂，增加崩解速度，还能增强片剂的机械强度、促进片剂的崩解，提高药物的溶出及生物利用度。其用量为 0. 5-2. 5%。 Sodium decyl sulfate: a water-soluble lubricant that can replace magnesium monostearate as a lubricant to increase the disintegration rate, enhance the mechanical strength of the tablet, promote the disintegration of the tablet, and improve the dissolution of the drug. bioavailability. 5%。 The amount is 0. 5-2. 5%.

本发明拟选择聚山梨酯 80为助崩剂，十二垸基硫酸钠为润滑剂。因药物为疏水性，故选择聚山梨酯 80作为助崩剂，又因我们拟选用的辅料如预胶化淀粉及微晶纤维素均属韧性较强的辅料，故选择十二烷基硫酸钠为润滑剂。 The invention intends to select polysorbate 80 as a disintegrating agent, and sodium dodecyl sulfate is a lubricant. Because the drug is hydrophobic, polysorbate 80 is selected as the disintegrating agent, and because the excipients we intend to use, such as pregelatinized starch and microcrystalline cellulose, are all tougher excipients, so sodium dodecyl sulfate is selected. For the lubricant.

1. 1. 5助流剂： 1. 1. 5 Glidant:

微粉硅胶（col loidal si l icon dioxide): 比表面积大，可达 100-350mVg，有良好的流动性，对药物有较大的吸附力，其亲水性强，用量在 1%以上时可加速片剂的崩解，有利药物的吸收，作助流剂用量一般仅为 0. 15-3%，用量在 1% 以上时可加速片剂的崩解。 Col loidal si l icon dioxide: large specific surface area, up to 100-350mVg, good fluidity, high adsorption capacity for drugs, strong hydrophilicity, accelerated when the dosage is above 1% The disintegration of the tablet is beneficial to the absorption of the drug, and the amount of the flow aid is generally only 0.15%, and the disintegration of the tablet can be accelerated when the dosage is above 1%.

本发明所述分散片处方的特点是联合应用大量的优质崩解剂和助悬剂；采用亲水性粘合剂的溶液；采用表面活性剂溶于粘合剂中使用；采用亲水性润滑剂。 The dispersible tablet formulation of the present invention is characterized by a combination of a large amount of high quality disintegrant and suspending agent; a solution using a hydrophilic binder; a surfactant dissolved in a binder; and a hydrophilic lubricant Agent.

方处 Everywhere

2. 药物与辅料的预处理 2. Pretreatment of drugs and excipients

《药典》规定，一般中药散剂的粉碎度为 "细粉"（即 80目粉或药典筛 5 号粉)，儿科用药粉碎成最细粉（100目粉或药典筛 6号粉)，本品是用分散片技术制备片剂，药物和辅料的粒度与溶出有一定影响，故处方筛选时粉碎细度定为 100目粉。 The Pharmacopoeia stipulates that the pulverization degree of the traditional Chinese medicine powder is "fine powder" (ie 80 mesh powder or Pharmacopoeia sieve No. 5 powder), and the pediatric medicine is pulverized into the finest powder (100 mesh powder or Pharmacopoeia sieve No. 6 powder), this product It is a tablet prepared by dispersing tablet technology, and the particle size and dissolution of the drug and the auxiliary material have a certain influence. Therefore, the fineness of the pulverization in the prescription screening is set to 100 mesh powder.

3. 片剂处方的初步筛选 3. Initial screening of tablet prescriptions

本研究主要针对填充剂和崩解剂的筛选，方法是在进行填充剂筛选时，将处方中崩解剂、润滑剂、助流剂、粘合剂四种成分固定；在进行崩解剂筛选时，其处方中的润滑剂、助流剂、粘合剂三种成分及用量与填充剂筛选处方相同，填充剂则是上述试验筛选出的辅料作为本处方的填充剂。根据文献调研的资料，填充剂筛选处方中，崩解剂是选择溶胀度最大的强崩解剂 CMS-Na，用量采用 8%，润滑剂选择十二垸基硫酸钠，用量为 0.5%，助流剂选择微粉硅胶，用量参考文献用量，并通过试验定为 1.3%, 粘合剂选择 3%PVPK₃。。 This study is mainly aimed at the screening of fillers and disintegrants by fixing the four components of disintegrants, lubricants, glidants and binders in the formulation of fillers. When the prescription, the three components and the amount of the lubricant, the flow aid and the adhesive are the same as the filler screening prescription, and the filler is the auxiliary agent selected by the above test as the filler of the prescription. According to the literature research, in the filler screening prescription, the disintegrant is the strong disintegrant CMS-Na with the highest degree of swelling. The dosage is 8%, and the lubricant is selected from sodium decyl sulfate. The dosage is 0.5%. The flow agent was selected as the micro-silica gel, the amount of reference was used, and the test was set to 1.3%, and the binder was 3% PVPK ₃ . .

3.1填充剂的筛选 3.1 screening of fillers

3.1.1表 2中的处方是按表中各成分的百分比计算 1000片用量，过 30目筛及湿颗粒 7CTC干燥的方法制成的片剂。表中为单一填充剂筛选， - 为微晶纤维素与其他四种填充剂搭配试验，因为微晶纤维素为多功能辅料同时具有填充、崩解、助流、粘合作用。 3.1.1 The prescription in Table 2 is a tablet made by the method of drying the 30 mesh sieve and the wet pellet 7CTC by the percentage of each component in the table. In the table, the single filler is screened, and the microcrystalline cellulose is tested with the other four fillers because the microcrystalline cellulose is a multifunctional auxiliary material with filling, disintegration, flow aid and adhesion.

表 2: 不同填充剂的处方 Table 2: Prescriptions for different fillers

填充剂崩解剂润滑剂助流剂粘合剂乳糖糖粉淀粉微晶纤预胶化十二垸基微粉硅 3%PVP (%) (%) (%) 维素 (%) 淀粉 (%) 硫酸钠 (%) 胶 (%) ₃₀(ιη1) Filler Disintegrant Lubricant Glidant Adhesive Lactose Syrup Powder Starch Microcrystalline Fiber Pregelatinized Twisted Dop Micropowder Silicon 3% PVP (%) (%) (%) Utilin (%) Starch (%) Sodium sulfate (%) Glue (%) ₃₀ (ιη1)

5 3%= 5 3%=

1 45.71 44.49 0.5 1.3 1 45.71 44.49 0.5 1.3

0.15g 6.6X3¾F 0.15g 6.6X33⁄4F

2 45.71 44.49 0.5 1.3 2 45.71 44.49 0.5 1.3

0.198g 0.198g

3 45.71 44.49 0.5 1.3 3 45.71 44.49 0.5 1.3

0.09g 0.09g

44.4 5+ 5X3¾F44.4 5+ 5X33⁄4F

4 45.71 0.5 1.3 4 45.71 0.5 1.3

9 0.665g 9 0.665g

7 3%= 7 3%=

5 45.71 44.49 0.5 1.3 5 45.71 44.49 0.5 1.3

0.21g 0.21g

22.2 22.2

6 45.71 22.24 0.5 1.3 6 45.71 22.24 0.5 1.3

0.21g 0.21g

7 45.71 22.24 22.24 0.5 1.3 6X3%= 0. 18g 7 45.71 22.24 22.24 0.5 1.3 6X3%= 0. 18g

3+ 5X 3¾F 45. 71 22. 24 22. 24 0. 5 1. 3 3+ 5X 33⁄4F 45. 71 22. 24 22. 24 0. 5 1. 3

0. 105g 45. 71 22. 24 22. 24 0. 5 1. 3 0. 105g 45. 71 22. 24 22. 24 0. 5 1. 3

0. 21g 注：在预筛选方中因粘合剂用量尚不知故未计入其内。 0. 21g Note: The amount of binder used in the pre-screening party is not counted in the unknown.

3. 1. 2按表 2制备的 9 个处方的片剂以硬度、崩解时限、药液分散情况为指标，考察其各种单独填充剂及填充剂的配比对片剂评价指标的影响。结果见表 3 表 3 : 填充剂筛选结果 3. 1. 2 According to the preparation of the 9 prescription tablets according to Table 2, the hardness, disintegration time limit, and dispersion of the drug were used as indicators. The effects of the ratio of various fillers and fillers on the evaluation indexes of the tablets were investigated. . The results are shown in Table 3 Table 3: Filler screening results

硬度崩解吋限 (秒） Hardness disintegration limit (seconds)

药液分散情况结果 (公斤力） 20°C士 1°C Dispersion of liquid solution Result (kg force) 20°C 1°C

2. 8、 3. 2、 2. 8,平均 2. 93,有顶 2. 8, 3. 2, 2. 8, average 2. 93, with top

60 呈球状膨胀崩解，分散均勾裂 60 is spherical expansion and disintegration, and the dispersion is split.

单独辅料 5. 4、 5. 4、 5. 3、 4. 2、 5. 0，平均 Separate excipients 5. 4, 5. 4, 5. 3, 4. 2, 5. 0, average

53 呈球状膨胀崩解，分散均匀 53 spheroidal expansion and disintegration, evenly dispersed

5. 06 筛选，处 5. 06 screening, at

1. 9、 3. 6、 3. 0,平均 2. 83 1032 缓慢溶解 1. 9, 3. 6, 3. 0, average 2. 83 1032 Slowly dissolve

方 2好顶裂 60 分散均匀 Square 2 good top crack 60 evenly dispersed

2. 0、 1. 5、 0,平均 1. 17 97 呈球状膨胀崩解，分散均匀 2. 0, 1. 5, 0, average 1. 17 97 Spherical expansion and disintegration, evenly dispersed

2. 0、 2. 3、 2. 2,平均 2. 17,有顶 2. 0, 2. 3, 2. 2, average 2. 17, top

69 呈球状膨胀崩解，分散均匀两种辅料 69 spheroidal expansion and disintegration, uniform dispersion

3. 3、 3. 4、 2. 6,平均 3. 10 95 呈球状膨胀崩解，分散均匀搭配，处3. 3, 3. 4, 2. 6, average 3. 10 95 spheroidal expansion and disintegration, evenly dispersed, match

4. 4、 4. 2、 4. 7,平均 4. 43 872 缓慢溶解 4. 4, 4. 2, 4. 7, average 4. 43 872 Slowly dissolve

方 9较好 2. 8、 3. 2、 3. 2, 平均 3. 07 59 呈球状膨胀崩解，分散均勾 Fang 9 is better 2. 8, 3. 2, 3. 2, average 3. 07 59 Spherical expansion and disintegration, scattered and ticked

3. 1. 3试验结果讨论 3. 1. 3 Discussion of test results

3. 1. 3. 1表 3表明，、 R₃、 R₄、片剂达不到要求，片剂硬度好崩解最快，药液分散均匀，但微晶纤维素价格高，流动性差，休止角为 51. 37 ° ，一般不单独使用。 3. 1. 3. 1 Table 3 shows that, R ₃ , R ₄ , tablets do not meet the requirements, the tablet hardness is good, the disintegration is the fastest, the liquid dispersion is uniform, but the microcrystalline cellulose is high in price and poor in fluidity. The angle of repose is 51.37 ° and is generally not used alone.

3. 1. 3. 2在两种填充剂搭配试验中，片剂顶裂， R₇、片剂崩解缓慢， R₉ 片剂崩解时间短且硬度在 3kg以上，崩解后溶液分散均匀，片剂中微晶纤维素与预胶化淀粉两种填充剂均有较好的塑性变形能力，且预胶化淀粉休止角为 36. 56° , 流动性较好，故选择处方 9。 3. 1. 3. 2 In the two filler matching tests, the tablet is cracked, R ₇ and the tablet disintegrate slowly, the R ₉ tablet has a short disintegration time and the hardness is more than 3 kg, and the solution is evenly dispersed after disintegration. The microcrystalline cellulose and the pregelatinized starch have good plastic deformation ability in the tablet, and the pre-gelatinized starch has an angle of repose of 36.56°, and the fluidity is good, so the prescription 9 is selected.

3. 2崩解剂的筛选 3. Screening of 2 disintegrants

3. 2. 1按表 4处方中各成分的百分比计算 1000片用量制成片剂（制备方法同填充剂筛选处方相同），在表 4中，崩解剂除以 CMS-Na， L-HPC, 交联 PVP , 分别进行试验外，还对 CMS-Na进行了搭配试验，因为文献报道 CMS-Na用量在 6% 以上，片剂明显吸潮***。表 4: 不同崩解剂处方 3. 2. 1 Calculate the dosage of 1000 tablets according to the percentage of each component in the prescription in Table 4 (the preparation method is the same as the filler screening prescription). In Table 4, the disintegrant is divided by CMS-Na, L-HPC. Cross-linked PVP was tested separately, and CMS-Na was also tested. Because the amount of CMS-Na was more than 6%, the tablets showed obvious moisture absorption and softening. Table 4: Different disintegrant prescriptions

填充剂崩解剂表面活隨助流剂处方药物 (%) 微晶纤预胶化 L-HPC CMS-Na 月桂醇硫微粉硅维素 (%) 淀粉 (%) (%) (%) 酸钠 (%) 胶（％) Filler disintegrant surface active with glidant prescription drug (%) microcrystalline fiber pregelatinized L-HPC CMS-Na lauryl sulphide micronized silicin (%) starch (%) (%) sodium (%) Glue (%)

1 45. 71 22. 24 22. 24 8 0. 5 1. 31 45. 71 22. 24 22. 24 8 0. 5 1. 3

2 45. 71 22. 24 22. 24 8 0. 5 1. 32 45. 71 22. 24 22. 24 8 0. 5 1. 3

3 45. 71 22. 24 22. 24 8 0. 5 1. 33 45. 71 22. 24 22. 24 8 0. 5 1. 3

4 45. 71 22. 24 22. 24 2 6 0. 5 1. 34 45. 71 22. 24 22. 24 2 6 0. 5 1. 3

5 45. 71 22. 24 22. 24 2 (外加） 6 0. 5 1. 35 45. 71 22. 24 22. 24 2 (plus) 6 0. 5 1. 3

3. 2. 2按表 4制备的 5 个处方的片剂以硬度、崩解时限、药液分散情况为指标，考察各种崩解剂的单独使用及搭配使用对片剂评价指标的影响。结果见表 5。 3. 2. 2 The five prescription tablets prepared according to Table 4 are based on the hardness, disintegration time limit, and dispersion of the drug solution. The effects of the individual use of the disintegrants and the combination on the evaluation indexes of the tablets were examined. The results are shown in Table 5.

表 5 : 崩解剂筛选试验结果 Table 5: Disintegrant screening test results

处方硬度（公斤力）崩解时限 (秒）崩解后药物分散情况结果Prescription Hardness (kg force) Disintegration time limit (seconds) Dispersion of drug after disintegration Result

1 3. 3、 3. 8、 3. 7,平均 3. 6 90 分散均匀 1 3. 3, 3. 8, 3. 7, average 3. 6 90 Disperse evenly

2 2. 8、 2. 5、 2. 8,平均 2. 7 90 呈大颗粒状 2 2. 8, 2. 5, 2. 8, average 2. 7 90 in large grain

处方 4、 Prescription 4,

3 3. 5、 4. 7、 5. 8,平均 4. 7 〉900 剩四个大颗粒 3 3. 5, 4. 7, 5. 8, average 4. 7 〉900 Four large particles left

5较好 5 is better

4 5. 0、 4. 2、 4. 7,平均 4. 6 47 呈球状崩解，分散均匀 4 5. 0, 4. 2, 4. 7, average 4. 6 47 spherical disintegration, evenly dispersed

5 4. 0、 3. 6、 3. 5,平均 3. 7 49 呈球状崩解，分散均匀 5 4. 0, 3. 6, 3. 5, average 3. 7 49 spherical disintegration, evenly dispersed

3. 2. 3试验结果分析 3. 2. 3 analysis of test results

3. 2. 3. 1表 5表明：崩解剂单独试验中片剂硬度较 R、略大，但崩解时限大于 15分钟，且有大颗粒存在。片剂硬度及崩解较好，溶液分散均匀。但中崩解剂为 CMS-Na, 有文献报道用量在 6%以上，片剂明显吸潮***。故拟考察崩解剂搭配试验。 3. 2. 3. 1 Table 5 shows: In the separate test of disintegrant, the tablet hardness is slightly larger than R, but the disintegration time limit is more than 15 minutes, and large particles are present. The tablet has good hardness and disintegration, and the solution is uniformly dispersed. However, the medium disintegrating agent is CMS-Na, and it has been reported in the literature that the dosage is above 6%, and the tablet obviously absorbs moisture and becomes soft. Therefore, it is planned to examine the disintegration test.

3. 2. 3. 2搭配试验表明： R₄、 R₆内加与外加差别不大，考虑到交联 PVP用量少，堆密度小，约 0. 26g/ml，若选用流化床制粒易分层被气流带走，因此确定外加（有文献报道内加 MCC，外加交联 PVP增加了单独应用效果），故选定 Rs中的崩解剂。 3. 2. 3. 2 The combination test shows that: R ₄ and R ₆ have little difference between the addition and the addition. Considering that the amount of cross-linking PVP is small, the bulk density is small, about 0. 26g/ml, if fluidized bed is used. The granules are easily separated by the gas stream, so it is determined to be added (there are reports that MCC is added in the literature, and the addition of cross-linked PVP increases the effect of the individual application), so the disintegrant in Rs is selected.

4. 处方优化 4. Prescription optimization

前述初筛选处方仅对辅料种类和基本用量进行考察，为了找出最佳的配比，采用正交设计试验进行优化（以 τ₅。为评价指标）。 The above-mentioned initial screening prescription only examines the types and basic amounts of excipients, in order to find the best ratio, Optimization was performed using orthogonal design experiments (with τ ₅ as the evaluation index).

4. 1片剂制备方法： 4. 1 tablet preparation method:

将处方中下列因素固定即药物 45. 71%、微粉硅胶 1. 30%、表面活性剂 0. 85% (其中聚山梨酯 80 0. 35%, 十二垸基硫酸钠 0. 5%)，另将预胶化淀粉作为 100% 总量调节辅料。这样考察的因素为三个因素①填充剂：微晶纤维素；②混合崩解剂（CMS-Na： PVPP=3： 1)； ③粘合剂为 PVPK₃。。选用 L_1S ( 3⁷)进行正交设计试验，每个处方制备片剂 2000片，试验结果见表。 The 5% of the drug is fixed in the prescription, that is, the drug is 45.71%, the micropowder silica gel is 1.30%, the surfactant is 0.85% (in which the polysorbate 80. 35%, the sodium dodecyl sulfate is 0.5%). Pregelatinized starch was also used as a 100% total amount of conditioning aid. The factors examined in this way were three factors: 1 filler: microcrystalline cellulose; 2 mixed disintegrant (CMS-Na: PVPP = 3: 1); 3 binder was PVPK ₃ . . The orthogonal design test was carried out using L _1S ( 3 ⁷ ), and 2000 tablets were prepared for each prescription. The test results are shown in the table.

4. 2溶出度试验操作： 4. 2 Dissolution test operation:

ZRS-4智能溶出仪，桨法，按溶出 2、 5、 10、 20、 30、 45分钟分别取样 5ml，用 0. 8 m孔径滤膜滤过，再吸取 0. 25ml样品于 5ml量瓶中，用溶出介质定容，以溶出介质为空白，测定吸收值（A) 求算 T₅。。 The sample was prepared by the method of the ZRS-4 intelligent dissolution apparatus, the paddle method, and the solution was taken for 5, 5, 10, 20, 30, and 45 minutes, and filtered by a 0.8 m pore size filter, and then the sample was taken up in a 5 ml volumetric flask. , dilute with the dissolution medium, take the dissolution medium as a blank, and measure the absorption value (A) to calculate T ₅ . .

4. 3正交试验设计安排表 4. 3 orthogonal test design schedule

表 6: 因素水平表 Table 6: Factor Level Table

因素 Factor

水平 Α崩解剂（％) 粘合剂（％) 微晶纤维素（％) C C) Horizontal Α disintegrator (%) binder (%) microcrystalline cellulose (%) C C)

CMS-Na： PVPP=3： 1 (A) (B ) CMS-Na: PVPP=3: 1 (A) (B )

1 6 1 18 1 6 1 18

2 8 3 21 2 8 3 21

3 10 5 24 3 10 5 24

表 7: L₁₈ ( 3⁷) 正交试验表 Table 7: L ₁₈ ( 3 ⁷ ) Orthogonal Test Table

A B A*B A*B C A*C A*C T50 Σ Τ50 列号 A B A*B A*B C A*C A*C T50 Σ Τ50 column number

1 1 1 1 1 1 1 1 10. 8 10. 7 10. 9 32. 51 1 1 1 1 1 1 1 1 10. 8 10. 7 10. 9 32. 51

16 92 03 16 92 03

2 1 2 2 2 2 2 2 9. 29 8. 37 8. 69 26. 36 2 1 2 2 2 2 2 2 9. 29 8. 37 8. 69 26. 36

97 06 07 1 97 06 07 1

3 1 3 3 3 3 3 3 7. 58 7. 17 7. 84 22. 60 3 1 3 3 3 3 3 3 7. 58 7. 17 7. 84 22. 60

82 32 1 82 32 1

4 2 1 1 2 2 3 3 11. 4 11. 2 10. 9 33. 60 4 2 1 1 2 2 3 3 11. 4 11. 2 10. 9 33. 60

44 21 42 6 44 21 42 6

5 2 2 2 3 3 1 1 9. 30 8. 26 7. 67 25. 24 5 2 2 2 3 3 1 1 9. 30 8. 26 7. 67 25. 24

97 41 16 5 97 41 16 5

6 2 3 3 1 1 2 2 9. 20 9. 59 9. 28 6 2 3 3 1 1 2 2 9. 20 9. 59 9. 28

82 86 19 9 82 86 19 9

7 3 1 2 1 3 2 3 12. 9 11. 4 10. 3 34. 80 7 3 1 2 1 3 2 3 12. 9 11. 4 10. 3 34. 80

76 83 45 4 76 83 45 4

8 3 2 3 2 1 3 1 9. 80 9. 32 9. 33 28. 46 26 1 73 18 3 2 3 2 1 3 1 9. 80 9. 32 9. 33 28. 46 26 1 73 1

9 3 3 1 3 2 1 2 10. 1 9. 05 9. 23 28. 39 9 3 3 1 3 2 1 2 10. 1 9. 05 9. 23 28. 39

01 75 24 1 01 75 24 1

10 1 1 3 3 2 2 1 10. 8 10. 8 8. 74 30. 43 10 1 1 3 3 2 2 1 10. 8 10. 8 8. 74 30. 43

17 75 63 8 17 75 63 8

11 1 2 1 1 3 3 2 9. 70 8. 81 10. 1 28. 66 11 1 2 1 1 3 3 2 9. 70 8. 81 10. 1 28. 66

6 77 43 7 6 77 43 7

12 1 3 2 2 1 1 3 10. 0 11. 3 11. 3 32. 86 12 1 3 2 2 1 1 3 10. 0 11. 3 11. 3 32. 86

78 96 92 6 78 96 92 6

13 2 1 2 3 1 3 2 15. 0 15. 9 15. 6 46. 42 13 2 1 2 3 1 3 2 15. 0 15. 9 15. 6 46. 42

13 49 61 3 13 49 61 3

14 2 2 3 1 2 1 3 9. 35 10. 2 9. 07 28. 70 14 2 2 3 1 2 1 3 9. 35 10. 2 9. 07 28. 70

49 81 29 9 49 81 29 9

15 2 3 1 2 3 2 1 7. 82 8. 23 8. 84 24. 90 15 2 3 1 2 3 2 1 7. 82 8. 23 8. 84 24. 90

56 56 51 6 56 56 51 6

16 3 1 3 2 3 1 2 10. 2 10. 3 9. 70 30. 27 16 3 1 3 2 3 1 2 10. 2 10. 3 9. 70 30. 27

4 36 14 7 4 36 14 7

17 3 2 1 3 1 2 3 12. 8 12. 1 11. 1 36. 11 17 3 2 1 3 1 2 3 12. 8 12. 1 11. 1 36. 11

32 25 53 32 25 53

18 3 3 2 1 2 3 1 8. 65 8. 28 8. 83 25. 77 18 3 3 2 1 2 3 1 8. 65 8. 28 8. 83 25. 77

57 12 31 57 12 31

I J 173. 208. 184. 178. 204. 178 167. I J 173. 208. 184. 178. 204. 178 167.

44 26 19 55 66 33 44 26 19 55 66 33

Il j 187. 173. 191. 176. 173. 180. 188. X Il j 187. 173. 191. 176. 173. 180. 188. X

18 55 67 48 28 71 41 yi=544. 435 18 55 67 48 28 71 41 yi=544. 435

Illj 183. 162. 168. 189. 166. 185. 188. CT=5489. 1 Illj 183. 162. 168. 189. 166. 185. 188. CT=5489. 1

81 62 58 41 5 73 7 81 62 58 41 5 73 7

Ssj= ( I j²+ Ssj= ( I j ² +

II j²+ III 5. 69 63. 0 15. 4 5. 36 46. 0 1. 70 16. 6 II j ² + III 5. 69 63. 0 15. 4 5. 36 46. 0 1. 70 16. 6

j²) / (6 X 3) 41 83 28 05 52 86 82 j ² ) / (6 X 3) 41 83 28 05 52 86 82

— CT — CT

表 8: 方差分析 Table 8: Analysis of Variance

方差来源自由度方差 F值显著性 Variance source degree of freedom variance F value significance

A 5. 694052 2 2. 847026 3. 570642 *A 5. 694052 2 2. 847026 3. 570642 *

B 63. 0829 2 31. 54145 39. 5582 **B 63. 0829 2 31. 54145 39. 5582 **

A*B 20. 78823 4 5. 197057 6. 517969 **A*B 20. 78823 4 5. 197057 6. 517969 **

C 46. 05246 2 23. 02623 28. 8787 **C 46. 05246 2 23. 02623 28. 8787 **

A*C 18. 39017 4 4. 597542 5. 766078 **A*C 18. 39017 4 4. 597542 5. 766078 **

SSe2 31. 09638 39 0. 797343 SSe2 31. 09638 39 0. 797343

正交试验表中就各因素 T₅。的单独作用作分析时，得到的最佳方案为 A Cs 这时通过方差分析 Α*Β及 A*C交互作用均有显著性，因此必须考虑 A和 B， A和 C的最优搭配，为此根据表中试验结果，列出下面二元表： A因素和 B因素的最优搭配分析表 The factors in the orthogonal test table are T ₅ . When the individual action is analyzed, the best solution is A Cs. At this time, the variance analysis Α*Β and A*C interactions are significant. Therefore, the optimal combination of A and B, A and C must be considered. Based on the test results in the table, the following binary table is listed: Analysis of the optimal combination of A factor and B factor

因素 B Factor B

因素 A Factor A

A_t (32. 51025+30. 43825) /2 (26. 3609十 28. 66705) /2= (22. 6058+32. 86615) /2=2A _t (32. 51025+30. 43825) /2 (26. 3609 10 28. 66705) /2= (22. 6058+32. 86615) /2=2

=31. 474 27. 51 7. 736 =31. 474 27. 51 7. 736

A₂ (33. 6058+46. 623) /2=40 (25. 24538+28. 7091) /2= (28. 08865+24. 90625) /2=A ₂ (33. 6058+46. 623) /2=40 (25. 24538+28. 7091) /2= (28. 08865+24. 90625) /2=

. 11 26. 977 26. 4975 11 26. 977 26. 4975

A₃ (34. 80405+30. 27725) /2 (28. 4609+36. 11) /2=32. (28. 39125+25. 76995) /2=A ₃ (34. 80405+30. 27725) /2 (28. 4609+36. 11) /2=32. (28. 39125+25. 76995) /2=

=32. 541 2850 27. 0806 =32. 541 2850 27. 0806

结果分析：根据数字愈小愈好， A和 B水平的最优搭配为 A₂B₃ Analysis of results: According to the smaller the number, the optimal combination of A and B levels is A ₂ B ₃

表 10: A因素和 C因素的最优搭配分析表 Table 10: Optimal collocation analysis table for A factor and C factor

因素 B Factor B

因素 A Factor A

C C₃ G CC ₃ G

A_t (32. 51025+30. 43825) /2= (26. 3609+30. 43825) /2=28 (22. 60125+28. 66705) /2=2 31. 474 . 399525 5. 63415 A _t (32. 51025+30. 43825) /2= (26. 3609+30. 43825) /2=28 (22. 60125+28. 66705) /2=2 31. 474 . 399525 5. 63415

(25. 24538+46. 623) /2=35 (33. 6058+28. 7091) /2=31. (25. 24538+24. 90625) /2=2 . 934 157 5. 0758 (25. 24538+46. 623) /2=35 (33. 6058+28. 7091) /2=31. (25. 24538+24. 90625) /2=2 . 934 157 5. 0758

(28. 4609+36. 11) /2=32. 2 (28. 39125+25. 76995) /2=2 (34. 80405+30. 27725) /2=3 85 7. 0806 2+ 54 (28. 4609+36. 11) /2=32. 2 (28. 39125+25. 76995) /2=2 (34. 80405+30. 27725) /2=3 85 7. 0806 2+ 54

结果分析： A*C水平的最优搭配为 A₂C₃ Analysis of results: The optimal combination of A*C levels is A ₂ C ₃

结论：初筛处方通过正交设计优化试验，其最佳处方组成为 AACJP崩解剂为总量 8% (CMS-Na： PVPP=3： 1 ) ; 粘合剂为 5% (PVPK₃。浓度为 5%); 微晶纤维素用量为总量的 24%。 Conclusion: The initial screening test was optimized by orthogonal design. The best prescription composition was AACJP disintegrant for 8% (CMS-Na: PVPP=3: 1); binder was 5% (PVPK ₃ . Concentration) 5%); microcrystalline cellulose is used in an amount of 24% of the total.

4. 4正交试验处方片剂其它指标质量的考察 4. 4 Orthogonal test prescription tablet quality of other indicators

注：水分是片剂成型不可缺少的因素，它可增加药物粒子的可塑性，减少弹性，防止裂片，并能减少颗粒间及与模圈壁的摩擦力，使颗粒排列更紧密，结合力更大。片剂硬度更大，我们从反复试验中找到了本制剂水分应控制在 3. 5%左右，表中列出的数据基本在此限度内。 Note: Moisture is an indispensable factor in tablet molding. It can increase the plasticity of the drug particles, reduce the elasticity, prevent the lobes, and reduce the friction between the particles and the wall of the mold ring, making the particles arranged more tightly and the bonding force is greater. . The hardness of the tablet is greater. We have found from the trial and error that the moisture of the preparation should be controlled at about 5%, and the data listed in the table is basically within this limit.

表 11 : 片剂崩解和脆碎度试验的结果表 Table 11: Results Table for Tablet Disintegration and Fragility Test

硬^ _ (公斤力） Hard ^ _ (kg force)

处方编号水分（％) 崩解时限（秒）脆碎度（％) Prescription number Moisture (%) Disintegration time limit (seconds) Fragility (%)

X ±SD X ±SD

3. 80 4. 08 ± 0. 342 65 0. 71 3. 85 4. 28 ± 0. 409 67 0 3. 55 4. 08 ± 0. 593 60 0 3. 80 4. 08 ± 0. 342 65 0. 71 3. 85 4. 28 ± 0. 409 67 0 3. 55 4. 08 ± 0. 593 60 0

3. 36 4. 62 ± 0. 084 65 03. 36 4. 62 ± 0. 084 65 0

4. 01 4. 26 ± 0. 114 55 0. 0144 2. 36 4. 00 ± 0. 394 59 0 7 3. 97 4. 50 ± 0. 394 57 0. 0854. 01 4. 26 ± 0. 114 55 0. 0144 2. 36 4. 00 ± 0. 394 59 0 7 3. 97 4. 50 ± 0. 394 57 0. 085

8 3. 19 3. 94 ± 0. 498 57 0. 1388 3. 19 3. 94 ± 0. 498 57 0. 138

9 3. 15 5. 16 ± 0. 351 67 0. 0679 3. 15 5. 16 ± 0. 351 67 0. 067

10 3. 30 4. 93 ±0. 27 75 10 3. 30 4. 93 ±0. 27 75

11 3. 40 3. 97 ±0. 35 46 11 3. 40 3. 97 ±0. 35 46

12 3. 51 4. 38 ±0. 46 101 12 3. 51 4. 38 ±0. 46 101

因为 10-18处方 Because 10-18 prescription

13 3. 30 4. 68 ±0. 45 81 13 3. 30 4. 68 ±0. 45 81

片剂压力与上基 Tablet pressure and foundation

14 3. 39 4. 17士 0. 41 65 14 3. 39 4. 17 士 0. 41 65

本相近，故末作 This is similar, so the end

15 3. 41 4. 24±0. 66 51 15 3. 41 4. 24±0. 66 51

脆碎度试验 Brittleness test

16 3. 10 4. 24士 0. 34 58 16 3. 10 4. 24 士 0. 34 58

17 3. 59 3. 91 ±0. 41 44 17 3. 59 3. 91 ±0. 41 44

18 3. 30 4. 31 ±0. 38 50 18 3. 30 4. 31 ±0. 38 50

4. 5处方的确定 4. 5 prescription determination

根据以上结果，确定本发明所述片剂处方如下： Based on the above results, the tablet formulation of the present invention was determined as follows:

黄芩总黄酮苷元 160g、微晶纤维素 84g、预胶化淀粉 62. 48g、羧甲基淀粉钠 21g、交联聚维酮 7g、十二垸基硫酸钠 1. 75g、聚山梨酯 80 1. 22g、微粉硅胶 4. 55g、聚维酮 K₃。 8g、蒸馏水适量，共制成 1000片。 Astragalus total flavonoid aglycone 160g, microcrystalline cellulose 84g, pregelatinized starch 62. 48g, carboxymethyl starch sodium 21g, crospovidone 7g, sodium dodecyl sulfate 1. 75g, polysorbate 80 1 22g, micro powder silica gel 4. 55g, povidone K ₃ . 8g, distilled water amount, a total of 1000 pieces.

实验例 2: 本发明颗粒及片剂引湿性考査： Experimental Example 2: Examination of the wettability of the granules and tablets of the present invention:

1、颗粒及片剂引湿性考察方法是同时进行的，但称量瓶中的样品分别为 lg/ 瓶、 5片 /瓶，试验结果如下。 1. The method for examining the wettability of granules and tablets was carried out simultaneously, but the samples in the weighing bottles were lg/bottle, 5/cell, respectively. The test results are as follows.

试验方法：将 6个盛有恒湿溶液的干燥器放入 LRH-150B 生化培养箱中，在 25 °C恒湿 24小时，再将 6个 35 X 25的称量瓶（已称重）按干燥器相应的 RH% 进行编号，分别放入干燥器中，在 25°C恒温加湿 7天，精密称定，计算吸湿量，计算不同相对湿度条件下样品的吸湿率（％) (25°C ), 以平衡吸湿率为纵坐标，以相对湿度为横坐标，绘制吸湿曲线图，确定临界相对湿度。 Test method: Put 6 desiccants with constant humidity solution into the LRH-150B biochemical incubator, keep it at 25 °C for 24 hours, then press 6 35 X 25 weighing bottles (weighed) according to the dryer. The corresponding RH% are numbered, placed in a desiccator, humidified at 25 °C for 7 days, accurately weighed, calculate the moisture absorption, calculate the moisture absorption rate (%) (25 ° C) of the sample under different relative humidity conditions, The equilibrium moisture absorption rate is plotted on the ordinate and the relative humidity is plotted on the abscissa. The moisture absorption curve is drawn to determine the critical relative humidity.

黄芩总黄酮干颗粒吸湿试验结果：见表 12及附图 1。 The results of moisture absorption test of total flavonoids of Astragalus membranaceus: See Table 12 and Figure 1.

表 12: 干颗粒吸湿实验结果表 Table 12: Dry granule moisture absorption test results table

相对湿度％吸湿率％ Relative humidity % moisture absorption rate %

21. 53 2. 42794 21. 53 2. 42794

29. 55 2. 47297 29. 55 2. 47297

40. 52 2. 75276 40. 52 2. 75276

57. 70 2. 98013 57. 70 2. 98013

75. 28 4. 97138 75. 28 4. 97138

84. 26 6. 93069 本发明片剂吸湿实验结果：见表 13及附图 2。表 13: 片剂吸湿实验结果表 84. 26 6. 93069 Results of the moisture absorption test of the tablet of the present invention: See Table 13 and Figure 2. Table 13: Tablet moisture absorption test results table

相对湿度％吸湿率％ Relative humidity % moisture absorption rate %

21. 53 1. 96448 21. 53 1. 96448

29+ 55 1. 98638 29+ 55 1. 98638

40. 52 2. 53063 40. 52 2. 53063

57. 70 2. 72608 57. 70 2. 72608

75. 28 4. 79090 75. 28 4. 79090

84. 26 7. 21815 84. 26 7. 21815

3. 2试验结果与讨论：实验结果表明，干颗粒及片剂的临界相对湿度（CRH%) 均为 57. 7%，故生产车间的相对湿度（25 °C ) 应控制在 57. 7%以下，包装及贮存应密闭、干燥。 The test results show that the relative humidity (CRH%) of the dry granules and tablets is 57.7%, so the relative humidity of the production workshop (25 °C) should be controlled at 57.7%. Below, packaging and storage should be sealed and dry.

实验例 3_: 急性毒性试验 Experimental Example 3 _: Acute toxicity test

一日内给小鼠灌胃本发明实施例 1所制分散片的提取物，为 60. 0g/kg，相当于临床 70kg人每公斤体重日用量的 8400倍以上；一日内给小鼠腹腔注射经痛舒片提取物为 5. Og/kg, 相当于临床 70kg人每公斤体重日用量的 700倍以上；连续观察七天,小鼠一般状况良好,无一死亡，说明本品低毒、安全。 The extract of the dispersible tablet prepared in Example 1 was administered to a mouse in a day, which was 60. 0 g/kg, which was equivalent to more than 8400 times of the daily dose of 70 kg of human body per kilogram of body weight; intraperitoneal injection of menstrual pain in a day The extract of Shushu is 5. Og/kg, which is equivalent to 700 times of the daily dose of 70 kg of human body per kilogram of body weight; for seven days in a row, the mice are generally in good condition and none die, indicating that the product is low in toxicity and safe.

实验例 4: 长期毒性试验 Experimental Example 4: Long-term toxicity test

( 1 )给大鼠灌胃经痛舒片提取物 0. 42g/kg、 0. 21g/kg、 0. 07g/kg鼠重，相当于 70kg人临床日用量的 60倍、 30倍、 10倍，连续给药 45天，观察动物一般状况、体重变化、食量、水量，试验结束后，分别检测血液学、血生化学指标; 并活杀 2/3动物，检测重要脏器的脏器系数和组织病理学的改变。剩余 1/3动物，进行 21天恢复期观察，复测上述指标，均未发现明显的毒副作用和继发、后遗的毒性反应，说明本药拟采用的临床用药剂量和疗程安全、低毒。 (1) Rats were given a dose of 0. 42g/kg, 0. 21g/kg, and 0.07g/kg of rats, which is equivalent to 60 times, 30 times, and 10 times of the clinical daily dose of 70kg. Continuous administration for 45 days, observe the general condition, weight change, food intake, water volume of the animals. After the test, hematology and blood biochemical indicators were detected respectively; and 2/3 animals were killed, and the organ coefficients and tissues of important organs were detected. Pathological changes. The remaining 1/3 of the animals were observed for 21 days of recovery. After re-testing the above indicators, no obvious side effects and secondary and subsequent toxic reactions were found, indicating that the clinical dose and course of treatment to be used were safe and low-toxic. .

( 2 )给杂种犬喂饲本发明实施例 1所制分散片提取物 0. 42g/kg、0. 21g/kg、 0. 07g/kg犬重，相当于 70kg人临床日用量的 60倍、 30倍、 10倍，连续给药 42 天，观察动物一般状况、体重变化、食量、水量，试验结束后，分别检测血液学、血生化学、心电图指标；并活杀部分动物，检测重要脏器的脏器系数和组织病理学的改变。剩余动物，进行 21天恢复期观察，复测上述指标，均未发现明显的毒副作用和继发、后遗的毒性反应，说明本药拟采用的临床用药剂量和疗程安全、低毒。 (2) feeding the hybrid dog with the dispersible tablet extract of the present invention in Example 1. 0. 42g / kg, 0. 21g / kg, 0. 07g / kg dog weight, equivalent to 60 times the clinical daily dose of 70kg, 30 times, 10 times, continuous administration for 42 days, observe the general condition, weight change, food intake, water volume of the animals. After the test, hematology, blood chemistry and electrocardiogram indicators were detected respectively; and some animals were killed and important organs were detected. Organ coefficient and histopathological changes. The remaining animals were observed for 21 days of recovery, and the above indicators were retested. No obvious side effects and secondary or subsequent toxic reactions were found, indicating that the clinical dose and course of treatment to be used were safe and low-toxic.

实验例 5: I期临床试验共有 35例女性自愿者参加， 5例受试者不符合入选标准而未入选。 30例健康受试者试验完成而正常终止。 Experimental Example 5: Phase I clinical trial A total of 35 female volunteers participated, and 5 subjects did not meet the inclusion criteria and were not selected. Thirty healthy subjects were successfully terminated after the trial was completed.

结果： Result:

1.单次口服 SG001 80mg-1280mg,最高剂量达到临床推荐给药剂量的 8. 0倍，无明显不良反应。因此，在本研究所设定的剂量范围内，受试者对该药可耐受，该药是安全的。 1. Single oral administration of SG001 80mg-1280mg, the highest dose reached 8.0 times the clinical recommended dose, no obvious adverse reactions. Therefore, within the dose range set by the Institute, the subject is tolerant to the drug and the drug is safe.

2.口服 SG001 160mg-640mg, 3次 /日， 7天，最高剂量达到临床推荐给药剂量的 4. 0倍，无明显不良反应。因此，在本研究所设定的剂量、疗程范围内，受试者对该药可耐受，该药是安全的。 2. Oral SG001 160mg-640mg, 3 times / day, 7 days, the highest dose reached 0.4 times the clinical recommended dose, no obvious adverse reactions. Therefore, the subject is tolerant to the drug within the dose and course of treatment set in this study, and the drug is safe.

3.可进行 II期临床，推荐剂量 160mg- 640mg。 3. Can be phase II clinical, the recommended dose is 160mg-640mg.

实验例 6: II期临床试验 Experimental Example 6: Phase II clinical trial

总体设计：采用剂量平行对照、分层随机、双盲、多中心临床试验设计方法，试验共入选 240例病例，年龄最小者 18岁，最大者 35岁，平均年龄 25岁。 Overall design: A parallel-controlled, stratified randomized, double-blind, multicenter clinical trial design approach was used. A total of 240 patients were enrolled. The youngest was 18 years old, the youngest was 35 years old, and the average age was 25 years.

治疗方案：分 3组，分别为低剂量组，高剂量组，安慰剂组。每个*** 的月经前 5天开始服药， 2片 /次， 3次 /日，连服 7天，连用 3个***。对痊愈病例随访 3个***。 Treatment options: divided into 3 groups, low dose group, high dose group, placebo group. The drug was started 5 days before menstruation in each menstrual cycle, 2 tablets/time, 3 times/day, and even served for 7 days, and used for 3 menstrual cycles. The recovery cases were followed up for 3 menstrual cycles.

临床试验结果： Clinical trial results:

( 1 ) 疼痛程度疗效方面，三组基线均衡，在服药 3个***时，对三组的疗效进行两两比较，发现差异均有统计学显著性意义，三组疗效差异显著，高剂量组疗效最好，达 98°/。，低剂量组其次，为 90%, 安慰剂组最差，为 40%。高剂量组疼痛程度改善接近 4分，低剂量组改善 3分左右，安慰剂组改善不足 2 分。 (1) In terms of the degree of pain, the three groups were balanced at baseline. When the menstrual cycle was 3 months, the effects of the three groups were compared. The difference was statistically significant. The three groups had significant differences. The high dose group The best effect, up to 98 ° /. The low dose group was 90%, and the placebo group was the worst, 40%. In the high-dose group, the pain level improved by nearly 4 points, the low-dose group improved by about 3 points, and the placebo group improved by less than 2 points.

(2 )痊愈患者随访疗效方面，服药 3个***时，低剂量组有 10例病例痊愈，高剂量组有 10例病例痊愈，安慰剂组有 1例病例痊愈。对痊愈患者进行随访，又经过 3个***后，低剂量组有 2例出现疼痛，高剂量组有 1例出现疼痛，安慰剂组未出现疼痛病例。 (2) In terms of follow-up efficacy of patients with recovery, 10 patients in the low-dose group recovered in the 3 menstrual cycle, 10 patients recovered in the high-dose group, and 1 patient recovered in the placebo group. Follow-up of the recovery patients, after 3 menstrual cycles, 2 patients in the low-dose group developed pain, 1 patient in the high-dose group, and no pain in the placebo group.

(3 ) 安全性：三组治疗前后的生命体征均没有统计学显著性意义的变化，共发生不良事件 12例，其中低剂量组 4例，高剂量组 3例，安慰剂组 5例，均为较轻微的头晕、恶心。不良事件发生情况组间差异无统计学显著性意义。说明本品安全性很高。 (3) Safety: There were no statistically significant changes in vital signs before and after treatment. There were 12 adverse events, including 4 in the low-dose group, 3 in the high-dose group, and 5 in the placebo group. For a slight dizziness, nausea. There were no statistically significant differences between the groups in the incidence of adverse events. Description This product is very safe.

与现有技术相比，本发明将黄芩总黄酮苷元为原料制成的药物，具有清热祛湿、理血止痛的作用，能有效治疗痛经；同时根据黄芩总黄酮苷元的特性和临床用药需要，以微晶纤维素、预胶化淀粉为填充剂，以聚维酮 K-30为粘合剂，以交联聚维酮、羧甲基淀粉钠为崩解剂，以十二垸基硫酸钠、聚山梨脂 -80为辅助崩解剂，滑石粉为助流剂，制成的分散片剂质量稳定可控，药物溶出度高、崩解快、疗效好安全性高，副作用小，且所述片剂工艺方法简单，易于操作，得率高（达 10%)，适合工业化生产，达到了发明目的。 Compared with the prior art, the invention has the medicine of preparing total flavonoid aglycone of astragalus as raw material, has the functions of clearing away heat and dampness, regulating blood and relieving pain, and can effectively treat dysmenorrhea; and according to the characteristics and clinical use of total flavonoid aglycone of astragalus Need, microcrystalline cellulose, pregelatinized starch as filler, povidone K-30 as binder, crospovidone, sodium carboxymethyl starch as disintegrant, Sodium sulphate and polysorbate-80 are auxiliary disintegrants, and talcum powder is a glidant. The quality of the dispersed tablets is stable and controllable. The drug has high dissolution rate, rapid disintegration, good efficacy, high safety and side effects. Moreover, the tablet process method is simple, easy to operate, high yield (up to 10%), suitable for industrial production, and achieves the object of the invention.

附图说明 DRAWINGS

图 1是干颗粒吸湿平衡曲线图 Figure 1 is a dry particle moisture absorption balance curve

图 2是片剂吸湿平衡曲线图 Figure 2 is a graph of tablet moisture absorption balance

下面结合实施例对本发明作进一步的说明。 The present invention will be further described below in conjunction with the embodiments.

具体实施方式 detailed description

实施例 1 : Example 1

组方：黄芩总黄酮苷元 160g、微晶纤维素 84g、预胶化淀粉 62. 48g、羧甲基淀粉钠 21g、交联聚维酮 7g、十二烷基硫酸钠 1. 75g、聚山梨酯 80 1. 22g、滑石粉 4. 55g、聚维酮 K₃。 8g。 The prescription: Astragalus total flavonoid aglycone 160g, microcrystalline cellulose 84g, pregelatinized starch 62. 48g, sodium carboxymethyl starch 21g, crospovidone 7g, sodium lauryl sulfate 1. 75g, poly sorbate Ester 80 1. 22 g, talc 4.55 g, povidone K ₃ . 8g.

工艺：所述分散片这样制备： Process: The dispersible tablet is prepared as follows:

C、将 A品和 B品混合，加入 B品 0. 06倍量的蒸馏水搅拌，制粒，得颗粒，为 C品 C. Mix A and B, add B. 0. 06 times the amount of distilled water, stir, granulate, get granules, be C

使用方法：口服，一次 1片，一日 3次。 How to use: Oral, 1 tablet at a time, 3 times a day.

实施例 2: Example 2:

组方：黄芩总黄酮苷元 170g、微晶纤维素 90g、预胶化淀粉 70g、羧甲基淀粉钠 25g、交联聚维酮 10g、十二垸基硫酸钠 5g、聚山梨酯 80 5g、滑石粉 5g、聚维酮 K₃。 10go The prescription: Astragalus total flavonoid aglycon 170g, microcrystalline cellulose 90g, pregelatinized starch 70g, carboxymethyl lake 25 g of sodium powder, 10 g of crospovidone, 5 g of sodium decyl sulfate, 80 g of polysorbate, 5 g of talc, and povidone K ₃ . 10go

B、称取过 120目筛的黄芩总黄酮苷元，加微晶纤维素、预胶化淀粉和羧甲基淀粉钠，于混合制粒机中混合均匀，得 B品； B. Weigh the total flavonoid aglycon of Astragalus membranaceus with 120 mesh sieve, add microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and mix well in a mixing granulator to obtain B product;

C、将 A品和 B品混合，加入 B品 1倍量的水搅拌，制粒，得颗粒，为 C品； C. Mix the product A and the product B, add 1 time of water, stir, granulate, and obtain granules, which are C products;

D、取 C品于 80°C的温度下干燥 4小时，干燥后的颗粒用 40目筛整粒后，加入交联聚维酮及滑石粉过筛混合均匀，调整片重为 0. 35g，压片，即得。 The granules are adjusted to a weight of 0.35 g, and the granules are granulated with a granule. Tableting, that is.

实施例 3: Example 3:

组方：黄芩总黄酮苷元 150g、微晶纤维素 80g、预胶化淀粉 60g、羧甲基淀粉钠 15g、交联聚维酮 lg、十二垸基硫酸钠 0. lg、聚山梨酯 80 0. 5g、滑石粉 3g、聚维酮 Kso lg。 The prescription: Astragalus total flavonoid aglycon 150g, microcrystalline cellulose 80g, pregelatinized starch 60g, carboxymethyl starch sodium 15g, crospovidone lg, sodium dodecyl sulfate 0. lg, polysorbate 80 0. 5g, talc powder 3g, povidone Kso lg.

B、称取过 80目筛的黄芩总黄酮苷元，加微晶纤维素、预胶化淀粉和羧甲基淀粉钠，于混合制粒机中混合均匀，得 B品； B. Weigh the total flavonoid aglycone of Astragalus membranaceus with 80 mesh sieve, add microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and mix well in the mixing granulator to obtain B product;

C、将 A品和 B品混合，加入 B品 0. 03倍量的水搅拌，制粒，得颗粒，为 C 品； C. Mix A and B, add B. 0. 03 times the amount of water to stir, granulate, and obtain granules, which are C;

D、取 C品于 60°C的温度下干燥 2小时，干燥后的颗粒用 20目筛整粒后，加入交联聚维酮及滑石粉过筛混合均匀，调整片重为 0. 3g，压片，即得。 The slab weight is 0. 3g,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Tableting, that is.

实施例 4: Example 4:

组方：黄芩总黄酮苷元 170g、微晶纤维素 90g、预胶化淀粉 60g、羧甲基淀粉钠 15g、交联聚维酮 10g、十二垸基硫酸钠 0. lg、聚山梨酯 80 5g、滑石粉 5g、聚维酮 K₃。 lg。工艺：所述分散片这样制备： The prescription: Astragalus total flavonoid aglycone 170g, microcrystalline cellulose 90g, pregelatinized starch 60g, carboxymethyl starch sodium 15g, crospovidone 10g, sodium dodecyl sulfate 0. lg, polysorbate 80 5 g, talc 5 g, povidone K ₃ . Lg. Process: The dispersible tablet is prepared as follows:

C、将 A品和 B品混合，加入 B品 0. 08倍量的水搅拌，制粒，得颗粒，为 C 品； C. Mix A and B, add B. 0. 08 times the amount of water to stir, granulate, and obtain granules, which is C;

D、取 C品于 75°C的温度下干燥 2. 5小时，干燥后的颗粒用 35目筛整粒后，加入交联聚维酮及滑石粉过筛混合均匀，调整片重为 0. 4g，压片，即得。 D, taking C product at a temperature of 75 ° C for 2. 5 hours, after drying the granules with a 35 mesh sieve granules, adding crospovidone and talc sifted and mixed evenly, adjust the tablet weight to 0. 4g, tablet, that is.

实施例 5: Example 5

所述黄芩总黄酮苷元的制备方法为：取黄芩药材，粉碎为粗粉，加入 6倍量煮沸后冷却至 35°C的水，搅拌均勾，加盖密封，静置 24小时取出于 65°C烘干，照流浸膏和浸膏剂项的渗漉法，加入 1倍量乙醇，搅拌均匀，润湿装入渗漉筒，加入 5倍量乙醇密封浸泡，继续加至 12倍量的乙醇渗漉，渗漉液减压回收至相对密度为 1. 01-1. 04，趁热加入 1. 5倍量冷水静置 12小时，抽滤，粗结晶以适量水洗涤，于 65°C烘干即得。 The preparation method of the total flavonoid aglycone of Astragalus membranaceus is: taking the Astragalus membranaceus medicinal material, pulverizing into a coarse powder, adding 6 times of boiling water, cooling to 35 ° C, stirring, hooking, sealing, and standing for 24 hours, taken out at 65 °C drying, immersion method of extracting extract and extracting agent, adding 1 times of ethanol, stirring evenly, wetting into the percolating tube, adding 5 times of ethanol to seal and soaking, continue to add 12 times the amount The ethanol was percolated, and the percolate was recovered under reduced pressure to a relative density of 1. 01-1. 04, and the heat was added to 1.5 times the amount of cold water for 12 hours, suction filtration, and the crude crystals were washed with an appropriate amount of water at 65 ° C. Dry it.

Claims

权利要求书 Claim

1. 一种治疗痛经的药物，其特征在于：按照重量组份计算，由黄芩总黄酮苷元 150-170份、微晶纤维素 80-90份、预胶化淀粉 60-70份、羧甲基淀粉钠 15-25 份、交联聚维酮 1- 10份、十二垸基硫酸钠 0. 1-5份、聚山梨酯 80 0. 5-5份、滑石粉 3-5份和聚维酮 K₃。 1- 10份制成。 A medicine for treating dysmenorrhea, characterized in that: according to the weight component, 150-170 parts of total flavonoid aglycone, 80-90 parts of microcrystalline cellulose, 60-70 parts of pregelatinized starch, and carboxymethyl group 15-25 parts of sodium starch, 1 - 10 parts of crospovidone, 0. 1-5 parts of sodium decyl sulfate, 80. 5-5 parts of polysorbate, 3-5 parts of talc and poly Vesone K ₃ . Made from 1 to 10 parts.

2. 根据权利要求 1所述治疗痛经的药物，其特征在于：按照重量组份计算，由黄芩总黄酮苷元 160份、微晶纤维素 84份、预胶化淀粉 62. 48份、羧甲基淀粉钠 21份、交联聚维酮 7份、十二垸基硫酸钠 1. 75份、聚山梨酯 80 1. 22份、滑石粉 4. 55份和聚维酮 Κ₃。 8份制成。 The medicine for treating dysmenorrhea according to claim 1, characterized in that: 160 parts of total flavonoid aglycone, 84 parts of microcrystalline cellulose, 62.48 parts of pregelatinized starch, and carboxymethyl group are calculated according to the weight component. 21 parts of sodium starch, 7 parts of crospovidone, 1.75 parts of sodium dodecyl sulfate, 120 parts of polysorbate 80, 2.5 parts of talc, and povidone oxime ₃ . Made in 8 parts.

3. 根据权利要求 1或 2所述治疗痛经的药物，其特征在于：所述药物的剂型为分散片。 The medicament for treating dysmenorrhea according to claim 1 or 2, wherein the pharmaceutical is in the form of a dispersion sheet.

4. 根据权利要求 3所述治疗痛经的药物的制备方法，其特征在于：所述分散片这样制备： The method for preparing a medicament for treating dysmenorrhea according to claim 3, wherein the dispersible tablet is prepared as follows:

Α、称取十二垸基硫酸钠、聚山梨酯 80和聚维酮 Κ₃。配制成含聚维酮 Κ₃。为 5%的水溶液，为 Α品； Strontium, sodium dodecyl sulfate, polysorbate 80 and povidone oxime _{3 were} weighed. Formulated to contain povidone oxime ₃ . a 5% aqueous solution, which is a defective product;

C、将 A品和 B品混合，加入 B品 0. 03-1倍量的水搅拌，制粒，得颗粒，为 C 品； C. Mix product A and product B, add B product 0. 03-1 times the amount of water to stir, granulate, and obtain granules, which are C products;

D、取 C品于 60-8CTC的温度下干燥 2-4小时，干燥后的颗粒用 20-40目筛整粒后，加入交联聚维酮及滑石粉过筛混合均匀，压片，即得。 D, take C product to dry at 60-8CTC for 2-4 hours, dry the granules with 20-40 mesh sieve, add crospovidone and talcum powder and mix well, tablet, ie Got it.

5.根据权利要求 4所述治疗痛经的药物的方法，其特征在于：所述分散片这样制备：所述分散片这样制备： The method for treating a dysmenorrhea according to claim 4, wherein the dispersion sheet is prepared as follows: The dispersion sheet is prepared as follows:

A、称取十二垸基硫酸钠、聚山梨酯 80和聚维酮 K₃。配制成含聚维酮 Κ₃。为 5%的水溶液，为 Α品； A. Sodium dodecyl sulfate, polysorbate 80 and povidone K _{3 were} weighed. Formulated to contain povidone oxime ₃ . a 5% aqueous solution, which is a defective product;

B、称取过 100目筛的黄芩总黄酮苷元，加微晶纤维素、预胶化淀粉和羧甲基淀粉钠，于混合制粒机中混合均匀，得 B品； B. Weigh the total flavonoid aglycone of Astragalus membranaceus with 100 mesh sieve, add microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and mix well in the mixing granulator to obtain B product;

C、将 A品和 B品混合，加入 B品 0. 06倍量的蒸馏水搅拌，制粒，得颗粒，为 C 品； C, mixing product A and product B, adding B product 0. 06 times the amount of distilled water, granulation, granules, C Product

6.根据权利要求 4或 5所述治疗痛经的药物的制备方法，其特征在于：所述方法制备的片剂每片含汉黄芩素 C₁₆H₁₂0₅不少于 17. 5mg。 The production method 4 or 5, wherein the pharmaceutical treatment of dysmenorrhea claim, wherein: the method tablets prepared each containing Wogonin C ₁₆ H ₁₂ 0 ₅ less than 17. 5mg.

7.根据权利要求 4或 5所述治疗痛经的药物的方法，其特征在于：所述黄芩总黄酮苷元的制备方法为：取黄芩药材，粉碎为粗粉，加入 2-8 倍量煮沸后冷却至 25-45°C的水，搅拌均匀，加盖密封，静置 12-36小时取出于 55-8CTC烘干，照流浸膏和浸膏剂项的渗漉法，加入 0. 2-2倍量乙醇，搅拌均匀，润湿装入渗漉筒，加入 2-8倍量乙醇密封浸泡，继续加至 4-20倍量的乙醇渗漉，渗漉液减压回收至相对密度为 1. 01-1. 04，趁热加入 0. 5-3倍量冷水静置 4-18小时，抽滤，粗结晶以适量水洗涤，于 55-8CTC烘干即得。 The method for treating a dysmenorrhea according to claim 4 or 5, wherein the preparation method of the total flavonoid aglycone of the astragalus is: taking the radix astragali, pulverizing into a coarse powder, adding 2-8 times after boiling 2-2-2. 2-2 2-2 2-2 2-2 2-2 2-2 2-2 2-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Double the amount of ethanol, stir evenly, wet into the percolation tube, add 2-8 times the amount of ethanol to seal and soak, continue to add 4-20 times the amount of ethanol percolation, and the percolate is reduced to a relative density of 1. 01-1. 04, 趁热热0. 5-3 times the amount of cold water for 4-18 hours, suction filtration, coarse crystallization with appropriate amount of water, dried at 55-8CTC.