WO2019205959A1 - 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法 - Google Patents

一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法 Download PDF

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WO2019205959A1
WO2019205959A1 PCT/CN2019/082398 CN2019082398W WO2019205959A1 WO 2019205959 A1 WO2019205959 A1 WO 2019205959A1 CN 2019082398 W CN2019082398 W CN 2019082398W WO 2019205959 A1 WO2019205959 A1 WO 2019205959A1
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吕慧锋
胡小艳
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西安千禾药业股份有限公司
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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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
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    • 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
    • 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
    • A61K36/232—Angelica
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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)
    • A61K36/185—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)
    • A61K36/34—Campanulaceae (Bellflower family)
    • A61K36/344—Codonopsis
    • 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
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/69—Polygalaceae (Milkwort family)
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/74—Rubiaceae (Madder family)
    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
    • A61K36/8884—Arisaema, e.g. Jack in the pulpit
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/898—Orchidaceae (Orchid family)
    • A61K36/8988—Gastrodia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying

Definitions

  • the invention relates to the technical field of traditional Chinese medicine preparations, in particular to a pharmaceutical composition for treating epilepsy convulsion, convulsion in children, hemiplegia, and a preparation method thereof. More specifically, the medicine is an epilepsy capsule.
  • Epilepsy also known as "shofar wind” is a chronic brain disease characterized by abnormal discharge of brain neurons that causes transient central nervous system dysfunction. According to the latest epidemiological data in China, the overall prevalence of epilepsy in China is 7.0 ⁇ , the annual incidence rate is 28.8/100,000, and the prevalence of active epilepsy within one year is 4.6 ⁇ . According to this estimate, there are about 9 million epilepsy patients in China, of which 5 to 6 million are active epilepsy patients, and about 400,000 new epilepsy patients are added each year. In China, epilepsy has become the second most common neurological department after headache. disease.
  • epilepsy at home and abroad is mainly based on drug treatment.
  • Patients with epilepsy are treated with regular anti-epileptic drugs. About 70% of patients can be controlled by episodes. 50% to 60% of patients can be cured after 2 to 5 years of treatment. Patients can be treated like normal people. work and life. Therefore, reasonable and regular anti-epileptic drug treatment is the key.
  • Epilepsy "Su Wen” is called dysentery, that is, the lesion is in the dome (the brain).
  • Traditional Chinese medicine believes that its etiology and pathogenesis can be summarized as sputum, fire, shock, qi, blood and congenital factors, and it is always horrified, accumulated, and smoldering, especially among them.
  • Epileptic capsule is a medicine approved by the state for the treatment of epilepsy (standard number: WS-10525 (ZD-0525)-2002-2012Z, national medicine Zhunzi Z20025728), prescription: Astragalus 140g, Codonopsis 140g, Salvia miltiorrhiza 140g, Bupleurum 70g , Suanzaoren 105g, Polygala 70g, Gastrodia elata 105g, Uncaria 105g, Shichangpu 70g, Dannan Star 70g, Angelica 140g, Silkworm 105g, Liushen 70g, Yujin 70g, Licorice 70g, White Aconite 35g, made into 1000 capsules It has the effect of clearing the sputum, calming the nerves, calming the wind and relieving the phlegm. It is used for epileptic seizures caused by wind stagnation, convulsions in children, and facial spasm.
  • the existing preparation process of the epilepsy capsule produced by the prior art is as follows: the silkworm, the Liushen smashed into fine powder, sieved and spared; the remaining scutellaria and other fourteen flavors are boiled three times with water, the first time adding water 10 times the amount of boiling 2 Hours, the second addition of water 8 times the amount of boiling time 1.5 hours, the third time adding water 6 times the amount of boiling for 1 hour, the combined decoction, filtered, the filtrate was concentrated under reduced pressure to a relative density of 1.36 (60 ° C) thick paste Add the above fine powder, mix well, vacuum dry, pulverize into fine powder, wet granulation, dry at 70 ° C, and fill it into capsules to make 1000 capsules.
  • the inventor under the guidance of TCM theory, combined with the listed Chinese medicine
  • the Technical Guidelines for the Study of Production Process Change designed a new formulation for the Epileptic Capsule and proposed a new preparation method for the Epileptic Capsule.
  • the powder prepared in the filling process has a short tuning time, the material flow is even and smooth, and the adhesion powder punching condition is obviously improved, so that the filling process is stable, and the capsule loading amount after filling is small.
  • the number of employees and machine hours are reduced compared to the prior art.
  • Subsequent stability investigation found that the epilepsy capsule prepared by the invention is stable, and there is no problem such as moisture absorption and accumulation of the capsule contents.
  • a pharmaceutical composition for treating epileptic seizures, pediatric convulsions, hemifacial spasm, comprising medicinal herbs extracts and excipients; the excipients being selected from one or both of calcium carbonate and calcium hydrogen phosphate, the medicinal materials Based on the weight of the extract, the weight percentage of the excipient is 10%; the extract of the medicinal material is prepared by extracting the following Chinese medicinal materials:
  • the weight ratio of the auxiliary calcium carbonate and calcium hydrogen phosphate, calcium carbonate and calcium hydrogen phosphate is 1:1.
  • the parts by weight of the Chinese medicinal material are:
  • the medicinal material extract is prepared by the following method:
  • the pharmaceutical composition is a capsule, and the capsule contents are the herbal extract and the adjuvant.
  • Still another object of the present invention is to provide a method for preparing the above capsule, comprising the steps of:
  • the medicinal material extract is pulverized and passed through a sieve of 80-100 mesh to obtain a fine powder of the extract, which is reserved;
  • the ethanol is an aqueous ethanol solution having a volume percentage concentration of 80% to 85%.
  • a numerical value includes not only the numerical value itself but also all numerical values within the range of ⁇ 10%, preferably ⁇ 7%, more preferably ⁇ 5%.
  • the weight percentage of the excipient is 10% based on the weight of the medicinal material extract
  • the weight of the excipient is 9% to 11 by weight of the medicinal material extract.
  • % is preferably 9.3% to 10.7%, more preferably 9.5% to 10.5%.
  • the parts by weight are not the actual weight of the respective medicinal herbs, and the "parts by weight” is not an actual weight unit; the parts by weight represent the weight ratio relationship between the medicinal herbs.
  • 1 part by weight may be 1 kg, or 1 g, or 1 kg (500 g), or 10 g (as in the case of Example 1), and the like, depending on the actual situation.
  • the preparation method of the pharmaceutical composition and the capsule provided by the invention not only solves the difficulties in the process of the epileptic capsule preparation existing in the prior art, but also greatly saves the production cost, improves the production efficiency, and the stability of the capsule is Compared with the prior art epilepsy capsules, there is no problem such as moisture absorption and accumulation of the capsule contents.
  • Moisture absorption % (weight after moisture absorption - weight before moisture absorption) / weight before moisture absorption ⁇ 100%
  • the original drug powder has the highest moisture absorption rate, and it is obvious that the prior art uses the original drug powder as a preparation auxiliary.
  • the ratio refers to the weight percentage of the drug extract.
  • the moisture absorption rate of the composition is obviously related to the amount of the auxiliary material.
  • the moisture absorption rate of the composition is significantly lower than the composition of the auxiliary material amount of 5%.
  • the amount of the adjuvant is 10% by weight of the drug extract, and the adjuvant is selected from one or both of calcium carbonate and calcium hydrogen phosphate.
  • the adjuvant is used in an amount of 10% by weight of the drug extract, and the adjuvant is composed of calcium carbonate and calcium hydrogen phosphate.
  • the adjuvant is used in an amount of 10% by weight of the drug extract, and the adjuvant is composed of calcium carbonate and calcium hydrogen phosphate in a weight ratio of 1:1.
  • ethanol concentration that is, the volume percentage concentration of ethanol in an aqueous ethanol solution.
  • the results in Table 3 show that the granulation is carried out by using a 75% by volume aqueous solution of ethanol, and the particles are more, the cutting is difficult to control, and the difference in the amount of the mixture is large.
  • the granules are prepared by using a 90% by volume aqueous solution of ethanol, the fine powder is more, the powder is light, the feeding is difficult, and the loading varies greatly.
  • the granulation is carried out by using an aqueous ethanol solution having a volume percentage of 80% to 85%, and the blanking is normal, and the difference in the amount of the mixture is small. Therefore, it is preferably granulated in an aqueous ethanol solution having a volume percentage of 80% to 85%.
  • the operation was repeated 3 times, and the obtained capsules were designated as 20170305, 20170306, and 20170307, respectively.
  • Astragaloside IV China Food and Drug Control Research Institute 110781-200613, for content determination.
  • Protocatechuic aldehyde China National Institute for Food and Drug Control 110810-200506, for content determination.
  • Prior art epilepsy capsule three batches of capsules prepared according to the pharmaceutical standard WS-10525 (ZD-0525)-2002-2012Z, the batch numbers are 20170302, 20170303, 20170304, respectively.
  • Capsules prepared in Example 5 batch numbers were 20170305, 20170306, and 20170307, respectively.
  • the test was carried out according to the quality standard of estrus capsule WS-10525 (ZD-0525)-2002-2012Z.
  • the three batches of the capsules provided by the present invention have a smaller range of loading differences than the prior art epilepsy capsules. Both the accelerated stability study and the long-term stability study showed that the test data of the three batches of the prior art Epileptic Capsule and the capsule provided by the present invention all meet the quality standard requirements of the Epileptic Capsule, but during storage.
  • the capsule provided by the invention has better hygroscopicity than the prior art epilepsy capsule, and the variation of the disintegration time limit is small, and there is no problem such as moisture absorption and accumulation of the capsule contents. Therefore, the capsule provided by the present invention is more stable in quality.
  • the pharmaceutical composition, the capsule and the preparation method provided by the invention have a short adjustment time in the process of filling the capsule, and the adjustment time of each batch of the powder is shortened from 10 to 30 minutes to 10-15. Minutes, and the material flow is even and smooth, and the adhesion powder punching situation is obviously improved.
  • the number of employees and machine hours is reduced compared with the prior art process: filling a batch of material (about 420 kg) is shortened from 10 to 12 hours of the original process to about 8 hours.
  • the filling process is stable, and the range of capsule loading after filling is reduced, which is reduced from ⁇ 8% of the original process to ⁇ 5%.
  • the prescription of the pharmaceutical composition provided by the invention and the preparation method of the capsule not only solve the difficulty of the preparation existing in the prior art, the production cost is greatly saved, the production efficiency is improved, and the stability of the capsule is superior.
  • the prior art epilepsy capsules; the fluctuation of other various examination indexes are smaller than the prior art epilepsy capsules.

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Abstract

一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法，药物组合物包括药材提取物和辅料；所述药材提取物由黄芪、党参、丹参、柴胡、酸枣仁、远志、天麻、钩藤、石菖蒲、胆南星、当归、僵蚕、六神曲、郁金、甘草和制白附子制得；所述辅料为碳酸钙和/或磷酸氢钙，用量为药材提取物重量的10％，可改善药物的吸湿性、减小胶囊装量差异、提高胶囊剂的长期稳定性。

Description

一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法 技术领域
本发明涉及中药制剂技术领域，具体涉及一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法，更具体的，所述药物是痫愈胶囊。
背景技术
癫痫，又称为“羊角风”，是由大脑神经元异常放电，导致短暂的中枢神经系统功能失常为特征的慢性脑部疾病。据中国最新流行病学资料显示，国内癫痫的总体患病率为7.0‰，年发病率为28.8/10万，1年内有发作的活动性癫痫患病率为4.6‰。据此估计中国约有900万左右的癫痫患者，其中500～600万是活动性癫痫患者，同时每年新增加癫痫患者约40万，在中国癫痫已经成为神经科仅次于头痛的第二大常见病。
目前国内外对于癫痫的治疗主要以药物治疗为主。癫痫患者经过正规的抗癫痫药物治疗，约70％的患者其发作是可以得到控制的，其中50％～60％的患者经过2～5年的治疗是可以痊愈的，患者可以和正常人一样地工作和生活。因此，合理、正规的抗癫痫药物治疗是关键。
癫痫病《素问》称为巅疾，即病变部位在巅顶(即脑部)。中医认为其病因病机可概括为痰、火、惊、气、血和先天因素几个方面，总不离惊恐、积痰、火郁，而其中尤以积痰为主要。正如叶天士《临证指南医案·癫痫门》按语所云“痫症或由惊恐，或由饮食不节，或由母腹中受惊，以致脏气不平，经久失调，一触积痰，厥气内风，卒焉暴逆，莫能禁止，待其气反然后已。”另外，由于癫痫多是时发时止，且呈反复发作，日久必然影响到五脏的功能，导致五脏气血阴阳俱虚，即所谓“痫久必归五脏”，故多见虚实夹杂、正虚邪实的情况。因此，中医治疗癫痫一般以祛痰、息风、定惊为主要治则，同时兼顾病因病机的其它方面。
痫愈胶囊是国家批准上市的治疗癫痫的成药(标准编号：WS-10525(ZD-0525)-2002-2012Z，国药准字Z20025728)，处方为：黄芪140g、党参140g、丹参140g、柴胡70g、酸枣仁105g、远志70g、天麻105g、钩藤105g、石菖蒲70g、胆南星70g、当归140g、僵蚕105g、六神曲70g、郁金70g、甘草70g、制白附子35g，制成1000粒；具有豁痰开窍，安神定惊，息风解痉的功效，用于风痰闭阻所致的癫痫抽搐、小儿惊风、面肌痉挛。
现有工艺生产的痫愈胶囊现有制备工艺为：僵蚕、六神曲粉碎成细粉，过筛，备用；其余黄芪等十四味加水煎煮三次，第一次加水10倍量煎煮2小时，第二次加水8倍量煎煮次1.5小时，第三次加水6倍量煎煮1小时，合并煎液，滤过，滤液减压浓缩至相对密度为1.36(60℃)的稠膏，加入上述细粉，混合均匀，真空干燥，粉碎成细粉，湿法制粒，在70℃干燥，装入胶囊，制成1000粒，即得。
在生产实践中发现，按照上述制备方法，制粒后装胶囊过程中存在细颗粒易吸湿粘附粉冲杆，造成装量差异及频繁停机清理；而且制备得到的胶囊，在长期放置过程中存在胶囊内容物吸湿和积聚等问题。
发明内容
针对上述问题，通过处方研究、辅料筛选、工艺研究、产品小试，以及原工艺与优化后工艺大生产稳定性样品的对比研究；最终，发明人在中医理论的指导下，结合《已上市中药生产工艺变更研究技术指导原则》设计了所述痫愈胶囊的新的制剂处方并提出了所述痫愈胶囊的新的制备方法。按照新的制剂处方及制备方法制备得到的药粉在填充过程调机时间短，物料流动均匀流畅，粘附粉冲杆情况明显改善，从而使得填充过程稳定，填充后的胶囊装量差异范围小。另外，人员工时、机器工时均较现有技术有所减少。后续稳定性考察发现，本发明制备的痫愈胶囊稳定好，没有出现胶囊内容物吸湿和积聚等问题。
为了实现上述技术效果，本发明采用了如下的技术方案：
一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物，包括药材提取物和辅料；所述辅料选自碳酸钙和磷酸氢钙中的一种或两种，以所述药材提取物的重量为基准，所述辅料的重量百分比为10％；所述药材提取物由如下中药材经过提取制备得到：
黄芪、党参、丹参、柴胡、酸枣仁、远志、天麻、钩藤、石菖蒲、胆南星、当归、僵蚕、六神曲、郁金、甘草、制白附子。
优选的，所述辅料碳酸钙和磷酸氢钙，碳酸钙和磷酸氢钙的重量比为1:1。
优选的，所述中药材的重量份为：
黄芪140重量份、党参140重量份、丹参140重量份、柴胡70重量份、酸枣仁105重量份、远志70重量份、天麻105重量份、钩藤105重量份、石菖蒲70重量份、胆南星70重量份、当归140重量份、僵蚕105重量份、六神曲70重量份、郁金70重量份、甘草70重量份、制白附子35重量份。
优选的，所述药材提物物通过如下方法制备：
按照重量份准备各味药材；僵蚕、六神曲粉碎成细粉，过80～100目筛，备用；其余十四味药材加水煎煮三次，第一次加水10倍量煎煮2小时，第二次加水8倍量煎煮次1.5小时，第三次加水6倍量煎煮1小时，合并煎液，滤过，滤液减压浓缩至相对密度为1.36(60℃)的稠膏，加入所述细粉，混合均匀，干燥，即得。
优选的，所述药物组合物为胶囊剂，胶囊内容物为所述药材提取物和所述辅料。
本发明还有一个目的在于提供上述胶囊剂的制备方法，包括如下步骤：
I.将所述药材提取物粉碎，过80～100目筛，得到提取物细粉，备用；
II.将所述辅料粉碎(如有必要)，混合均匀；然后与步骤I得到的提取物细粉混合均匀；
III.向步骤II得到的混合细粉中适量乙醇，制粒，干燥，装胶囊，即得。
优选的，所述乙醇为体积百分比浓度80％～85％的乙醇水溶液。
在本说明书中，如果没有明确地规定，一个数值点，不仅仅包括该数值本身，还包括这个数值±10％，优选±7％，更优选±5％范围内的所有数值。例如，上文所述“以所述药材提取物的重量为基准，所述辅料的重量百分比为10％”，即是指所述辅料的重量为所述药材提取物的重量的9％～11％，优选为9.3％～10.7％，更优选为9.5％～10.5％。
本说明书中，所述重量份数不是所述各味药材的实际重量，“重量份”也不是一个实际的重量单位；重量份数表示的是各味药材之间的重量配比关系。根据实际情况，1重量 份可以是1kg，或者1g，或者1斤(500g)，或者10g(如实施例1所示的情形)，等等。
本发明提供的药物组合物及胶囊剂的制备方法不仅解决了现有技术中存在的痫愈胶囊制剂过程中存在的困难，大大节约了生产成本，提高了生产效率，而且胶囊剂的稳定性均优于现有技术的痫愈胶囊剂，没有出现胶囊内容物吸湿和积聚等问题。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材、辅料、试剂材料等，如无特殊说明，均为市售购买产品。
实施例1药材提物的制备
本实施例的所述药材提物，通过如下步骤制备：
1.取黄芪1400g(此处，1重量份＝10g，下同)、党参1400g、丹参1400g、柴胡700g、酸枣仁1050g、远志700g、天麻1050g、钩藤1050g、石菖蒲700g、胆南星700g、当归1400g、僵蚕1050g、六神曲700g、郁金700g、甘草700g、制白附子350g。
2.将僵蚕、六神曲粉碎成细粉，过80～100目筛，备用；
3.取其余黄芪等十四味药材加水煎煮三次，第一次加水10倍量煎煮2小时，第二次加水8倍量煎煮次1.5小时，第三次加水6倍量煎煮1小时，合并煎液，滤过，滤液减压浓缩至相对密度为1.36(60℃)的稠膏，加入步骤2制备得到的所述细粉，混合均匀，真空干燥，粉碎，过筛，即得。
实施例2所述药物组合物中辅料种类的筛选试验
取实施例1制备的药物提取物50g，平均分为6份，分别加入相同重量(5g)的可溶性淀粉、微晶纤维素、碳酸钙、磷酸氢钙、乳糖、原药粉(僵蚕和六神曲按照10.5:7的比例混合，粉碎，过筛)，分别记为1#(可溶性淀粉)，2#(微晶纤维素)，3#(碳酸钙)，4#(磷酸氢钙)，5#(乳糖)，6#(原药粉)，混合均匀，分别精密称取2g平摊于干燥至恒重的扁形称量瓶中，然后放置于底部盛有氯化钠过饱和溶液的玻璃干燥器中，在0，4，8，12，24，36，48，72，96h精密称重；每种辅料平行做3份，按照公式A计算吸湿百分率％，取平均值。结果见表1。
吸湿率％＝(吸湿后重量－吸湿前重量)/吸湿前重量×100％A
表1不同辅料的药物组合物吸湿百分率的测定结果(％，n＝3)
Figure PCTCN2019082398-appb-000001
Figure PCTCN2019082398-appb-000002
结果表明：相同的药物提物与不同辅料配伍后，得到的药物组合物吸湿性有显著的差异，吸湿率大小的排列顺序为：磷酸氢钙＜碳酸钙＜乳糖＜微晶纤维素＜可溶性淀粉＜原药粉。因此初步选择磷酸氢钙、碳酸钙作为辅料，进行下一步的研究。另外，原药粉的吸湿率最大，显然现有技术以原药粉作为制剂辅料是合适的。
实施例3辅料用量比例筛选试验
取实施例1制备的药物提取物8份(每份40g)，按照表2所示加入不同重量比例的碳酸钙和/或磷酸氢钙，混合均匀，分别精密称取2g平摊于干燥至恒重的扁形称量瓶中，防止于底部盛有氯化钠过饱和溶液的玻璃干燥器中放置24h，取出，再次精密称重；每种比例辅料平行做3份，按照公式A计算吸湿百分率％，取均值。结果见表2。
表2辅料配比/用量筛选试验结果
Figure PCTCN2019082398-appb-000003
a：所述比例是指占所述药物提取物的重量百分比。
表2的结果显示：
1)组合物的吸湿率与辅料的用量明显相关，辅料总用量为10％时，组合物的吸湿率显著低于辅料用量为5％的组合物。
2)在辅料总用量相同的情况下，碳酸钙和磷酸氢钙等量合用时，组合物的吸湿率最小。
因此，优选辅料用量是所述药物提取物重量的10％，所述辅料选自碳酸钙和磷酸氢钙中的一种或两种。
更优选的，所述辅料的用量是所述药物提取物重量的10％，所述辅料由碳酸钙和磷酸氢钙组成。
最优选的，所述辅料的用量是所述药物提取物重量的10％，所述辅料由重量比为1:1的碳酸钙和磷酸氢钙组成。
实施例4制粒所用乙醇水溶液的体积百分比浓度的筛选试验
取实施例1制备的所述药物提取物5000g，加入碳酸钙、磷酸氢钙各5％(以所述药物提取物的重量为基准)，混合均匀，平均分为4份，分别以体积百分比浓度75％、80％、85％、90％的乙醇水溶液制粒(每份用350ml)，过20目筛，填充于自动胶囊机，观察填充下料情况、测定装量差异。结果见表3。
表3润湿剂的确定
Figure PCTCN2019082398-appb-000004
b：乙醇浓度，即乙醇水溶液中乙醇的体积百分比浓度。
表3的结果显示：采用体积百分比75％的乙醇水溶液制粒，颗粒较多，下料不易控制，装量差异较大。采用体积百分比90％的乙醇水溶液制粒，细粉较多，药粉轻，下料困难，装量差异较大。采用体积百分比80％-85％的乙醇水溶液制粒，下料正常，装量差异小，因此，优选以体积百分比80％-85％的乙醇水溶液制粒。
实施例5本发明所述药物组合物胶囊剂的制备
黄芪140g、党参140g、丹参140g、柴胡70g、酸枣仁105g、远志70g、天麻105g、钩藤105g、石菖蒲70g、胆南星70g、当归140g、僵蚕105g、六神曲70g、郁金70g、甘草70g、制白附子35g，僵蚕、六神曲粉碎成细粉，过筛，备用；其余黄芪等十四味加水煎煮三次，第一次加水10倍量煎煮2小时，第二次加水8倍量煎煮次1.5小时，第三次加水6倍量煎煮1小时，合并煎液，滤过，滤液减压浓缩至相对密度为1.10～1.36(60℃)的稠膏，加入上述细粉，混合均匀，真空干燥，粉碎成细粉，共制备得到440g药物提物的细粉，与碳酸钙22g、磷酸氢钙22g混匀，用80％～85％乙醇适量制粒，在70～80℃干燥，装入胶囊，制成1000粒，即得。
重复操作3次，得到的胶囊剂分别记为20170305、20170306、20170307。
实施例6本发明所述药物胶囊剂的质量检测
仪器：
戴安Ultimate3000高效液相色谱仪系统及紫外检测器，安捷伦C18色谱柱(5μ，4.6×250mm)、UV-8三用紫外分析仪、水浴锅、烘箱、分析天平、崩解仪、干燥器、净化工作台、高压灭菌锅、培养箱等。
试剂：
三氯甲烷、正丁醇、氢氧化钠、乙醇、盐酸、乙酸乙酯、甲酸、三氯化铁、乙酸铵、冰醋酸、甲醇。
对照品：
黄芪甲苷：中国食品药品检定研究院110781-200613，供含量测定用。
原儿茶醛：中国食品药品检定研究院110810-200506，供含量测定用。
测试样品：
(1)现有技术的痫愈胶囊：按照药品标准WS-10525(ZD-0525)-2002-2012Z制备的三批胶囊，批号分别为20170302、20170303、20170304。
(2)实施例5制备的胶囊剂：批号分别为20170305、20170306、20170307。
试验方法：
按照痫愈胶囊质量标准WS-10525(ZD-0525)-2002-2012Z进行检测。
所有测试样品在相同条件下的0月及加速稳定性1个月、2个月、3个月、6个月，长期稳定性3个月、6个月的稳定测定结果分别见表4、表5、表6、表7、表8、表9、表10。
在0月及稳定性研究的各检测时间点，本发明提供的胶囊剂三批样品的装样差异范围都比现有技术的痫愈胶囊小。加速稳定性研究和长期稳定性研究结果均显示，现有技术的痫愈胶囊和本发明提供的胶囊剂三批样品各项检测数据虽然均符合痫愈胶囊的质量标准要求，但是在存放过程中，本发明提供的胶囊剂的吸湿性要优于现有技术的痫愈胶囊，崩解时限变化小，没有出现胶囊内容物吸湿和积聚等问题。因此，本发明提供的胶囊剂质量更稳定。
Figure PCTCN2019082398-appb-000005
Figure PCTCN2019082398-appb-000006
Figure PCTCN2019082398-appb-000007
Figure PCTCN2019082398-appb-000008
Figure PCTCN2019082398-appb-000009
Figure PCTCN2019082398-appb-000010
Figure PCTCN2019082398-appb-000011
经过大生产验证，本发明提供的所述药物组合物及胶囊剂及制备方法，在填充胶囊过程中调机时间短，每批药粉的调机时间由原来的20～30分钟缩短为10～15分钟，且物 料流动均匀流畅，粘附粉冲杆情况明显改善。人员工时、机器工时均较现有技术的工艺有所减少：填充一批物料(约420kg)由原工艺的10～12小时缩短为约8小时。填充过程稳定，填充后的胶囊装量差异范围缩小，由原工艺的±8％缩小为±5％。因此，本发明提供的药物组合物的处方及胶囊剂的制备方法不仅解决了现有技术中存在的制剂的困难，大大节约了生产成本，提高了生产效率，而且胶囊剂的稳定性均优于现有技术的痫愈胶囊剂；其它各项检查指标的波动均小于现有技术的痫愈胶囊。

Claims (8)

  1. 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物，包括药材提取物和辅料；所述辅料选自碳酸钙和磷酸氢钙中的一种或两种，以所述药材提取物的重量为基准，所述辅料的重量百分比为10％；所述药材提取物由如下中药材经过提取制备得到：
    黄芪、党参、丹参、柴胡、酸枣仁、远志、天麻、钩藤、石菖蒲、胆南星、当归、僵蚕、六神曲、郁金、甘草、制白附子。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述辅料碳酸钙和磷酸氢钙，碳酸钙和磷酸氢钙的重量比为1:1。
  3. 根据权利要求1所述的药物组合物，其特征在于，所述中药材的重量份为：
    黄芪140重量份、党参140重量份、丹参140重量份、柴胡70重量份、酸枣仁105重量份、远志70重量份、天麻105重量份、钩藤105重量份、石菖蒲70重量份、胆南星70重量份、当归140重量份、僵蚕105重量份、六神曲70重量份、郁金70重量份、甘草70重量份、制白附子35重量份。
  4. 根据权利要求1或3所述的药物组合物，其特征在于，所述药材提物物通过如下方法制备：
    按照重量份准备各味药材；僵蚕、六神曲粉碎成细粉，过80～100目筛，备用；其余十四味药材加水煎煮三次，第一次加水10倍量煎煮2小时，第二次加水8倍量煎煮次1.5小时，第三次加水6倍量煎煮1小时，合并煎液，滤过，滤液减压浓缩至相对密度为1.36(60℃)的稠膏，加入所述细粉，混合均匀，干燥，即得。
  5. 根据权利要求1至4中任一项所述的药物组合物，其特征在于，所述药物组合物为胶囊剂，胶囊内容物为所述药材提取物和所述辅料。
  6. 权利要求5所述的胶囊剂的制备方法，包括如下步骤：
    I.将所述药材提取物粉碎，过80～100目筛，得到提取物细粉，备用；
    II.如有必要，将所述辅料粉碎、混合均匀；然后与步骤I得到的提取物细粉混合均匀；
    III.向步骤II得到的混合细粉中适量乙醇，制粒，干燥，装胶囊，即得。
  7. 根据权利要求6所述的制备方法，其特征在于，所述乙醇为体积百分比浓度80％～85％的乙醇水溶液。
  8. 一种胶囊剂，根据权利要求6或7所述的制备方法制备得到的。
PCT/CN2019/082398 2018-04-26 2019-04-12 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法 WO2019205959A1 (zh)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1785409A (zh) * 2005-11-17 2006-06-14 西安千禾药业有限责任公司 一种治疗癫痫抽搐、小儿惊风、面肌痉挛的药物及其制备方法
CN1857694A (zh) * 2006-04-13 2006-11-08 贵州信邦制药股份有限公司 一种痫愈片中药复方制剂及其制备方法
CN103033587A (zh) * 2011-09-30 2013-04-10 西安千禾药业有限责任公司 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物的检测方法
CN104547882A (zh) * 2013-10-16 2015-04-29 西安千禾药业有限责任公司 一种治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物痫愈的制备方法
CN108420994A (zh) * 2018-04-26 2018-08-21 西安千禾药业股份有限公司 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1785409A (zh) * 2005-11-17 2006-06-14 西安千禾药业有限责任公司 一种治疗癫痫抽搐、小儿惊风、面肌痉挛的药物及其制备方法
CN1857694A (zh) * 2006-04-13 2006-11-08 贵州信邦制药股份有限公司 一种痫愈片中药复方制剂及其制备方法
CN103033587A (zh) * 2011-09-30 2013-04-10 西安千禾药业有限责任公司 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物的检测方法
CN104547882A (zh) * 2013-10-16 2015-04-29 西安千禾药业有限责任公司 一种治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物痫愈的制备方法
CN108420994A (zh) * 2018-04-26 2018-08-21 西安千禾药业股份有限公司 一种用于治疗癫痫抽搐、小儿惊风、面肌痉挛的药物组合物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JI, FENGHAI ET AL.: "Clinical Observation of Xianyu Capsules Combined with Magnesium Valproate in Treatment of Epilepsy", DRUGS & CLINIC, vol. 33, no. 4, 19 April 2018 (2018-04-19), pages 750 - 753 *

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