WO2024104417A1 - 一种氨磺必利片的制备方法 - Google Patents

一种氨磺必利片的制备方法 Download PDF

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Publication number
WO2024104417A1
WO2024104417A1 PCT/CN2023/131981 CN2023131981W WO2024104417A1 WO 2024104417 A1 WO2024104417 A1 WO 2024104417A1 CN 2023131981 W CN2023131981 W CN 2023131981W WO 2024104417 A1 WO2024104417 A1 WO 2024104417A1
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Prior art keywords
amisulpride
coating
tablets
preparation
coating material
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PCT/CN2023/131981
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English (en)
French (fr)
Inventor
宋以军
崔鑫萌
常德凯
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Hq Pharma Shandong Co Ltd
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Hq Pharma Shandong Co Ltd
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Priority to EP23858421.3A priority Critical patent/EP4393483A4/en
Publication of WO2024104417A1 publication Critical patent/WO2024104417A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the invention relates to the technical field of medicine preparation, and in particular to a method for preparing amisulpride tablets.
  • Amisulpride is an atypical antipsychotic drug that is mainly used to treat psychosis, specifically paranoid progressive schizophrenia, acute delirious psychosis, defective states of schizophrenia, residual psychotic evolution, and states of inhibition accompanied by blunting. It can also be used to treat prominent primary negative symptoms and depression.
  • Tableting is an essential process step in the production of oral solid dosage tablets.
  • sticking is very likely to occur during the tableting process, which will affect the properties of the plain tablets and may even affect the weight difference, resulting in unqualified content and content uniformity.
  • Mold coating may improve the problem of sticking.
  • the materials used for coating such as Teflon and chromium, are relatively expensive.
  • Moisture and particle size distribution The properties of the total mixed particles may also cause sticking, such as particle size distribution and moisture. However, this reason can only be controlled by most projects. For example, sticking caused by the properties of some raw materials will not be improved.
  • CN111728947A discloses an amisulpride tablet and a preparation method thereof.
  • the components of the amisulpride tablet include amisulpride, a binder, a filler, a disintegrant, a lubricant and an auxiliary lubricant.
  • the invention unexpectedly discovered that the addition of an auxiliary lubricant when preparing amisulpride tablets by a hot melt method solves the problem of sticking.
  • the amisulpride tablets prepared by the invention have a good solubility at a pH of 6.8, but their hardness is relatively low, which will cause the product to break during packaging and transportation, affecting product quality.
  • CN112535671A discloses a dispersible tablet of amisulpride and a preparation method thereof, wherein the active drug amisulpride is uniformly mixed with corresponding auxiliary materials, and granules are prepared by wet granulation process, and then the granules are coated by fluidized bed, and then mixed with other auxiliary materials and compressed into dispersible tablets.
  • the invention solves the sticking problem in the process of compressing amisulpride tablets, but the hardness of the tablets is low and the dissolution rate is affected.
  • auxiliary lubricants or auxiliary materials are added to the existing amisulpride tablet production.
  • the prepared tablets have problems such as low hardness and affected dissolution to varying degrees.
  • the present invention provides a method for preparing amisulpride tablets, which solves the problem that amisulpride is prone to sticking. At the same time, the prepared amisulpride tablets have high hardness and good solubility.
  • a method for preparing amisulpride tablets comprises the following steps: coating amisulpride with a coating material, and then selecting a hydrophilic lubricant to mix with the coated particles.
  • the coating material is at least two of sodium alginate, povidone, ion exchange resin, ethyl cellulose, cellulose acetate, and hydroxypropyl cellulose; more preferably, ethyl cellulose and hydroxypropyl cellulose; and even more preferably, the mass ratio of ethyl cellulose to hydroxypropyl cellulose is 1:1.
  • the amount of the coating material is 1-3% of the weight of the amisulpride tablets.
  • the hydrophilic lubricant is at least one of hard sodium fumarate, talc, sodium lauryl sulfate, micro powder silica gel, and polyethylene glycol; and hard sodium fumarate is most preferred.
  • the amount of the hydrophilic lubricant is 0.5-1.5% of the weight of the amisulpride tablets.
  • the process further comprises wet granulating amisulpride with a coating material to obtain wet granules.
  • the preparation method of amisulpride tablets specifically comprises the following steps:
  • step S2 coating: coating the wet granules obtained in step S1, drying, and granulating to obtain coated granules;
  • step S3 first mixing: mixing the coated granules obtained in step S2 with a hydrophilic lubricant to obtain material 1;
  • step S3 second mixing: add auxiliary materials to the material 1 obtained in step S3 and mix to obtain material 2;
  • step S4 total mixing: mixing the material 2 obtained in step S3 with the hydrophobic lubricant to obtain a total mixture;
  • step S5 tableting: tableting the total mixed material obtained in step S4 to obtain the amisulpride tablets.
  • the amount of the coating material in step S1 is 20-30% of the total coating material mass.
  • the auxiliary material in step S3 does not contain a lubricant.
  • the auxiliary material includes at least one of a disintegrant, a filler, a sweetener and a flavoring agent.
  • the hydrophobic lubricant in step S4 accounts for 0.5-1.5% of the weight of the amisulpride tablets.
  • the hydrophobic lubricant is at least one of magnesium stearate, calcium stearate, glycerol monostearate and stearic acid; most preferably magnesium stearate.
  • the hardness of the amisulpride tablets in step S5 is 50-80N.
  • the present invention provides a new solution to the sticking problem caused by the properties of amisulpride itself.
  • Amisulpride is coated with a polymer coating material, and a lubricant with good hydrophilicity is selected to mix with the coated particles. This method not only solves the problem of easy sticking of amisulpride, but also has high hardness and good solubility of the prepared amisulpride tablets.
  • FIG1 is a sticking diagram of amisulpride during tableting, wherein A is a sticking diagram of Example 1 of the present invention during tableting; and B is a sticking diagram of Comparative Example 1 of the present invention during tableting.
  • Example 1 A method for preparing amisulpride tablets
  • the prescription information of the amisulpride tablets is shown in Table 1.
  • the preparation method is:
  • Coating The wet granules are placed in a fluidized bed and coated using a fluidized bed top spray process. All coating materials are sprayed in and dried until the loss on drying is less than 3%. Drying is then stopped.
  • Second mixing Add the other excipients in the prescription except magnesium stearate to material 1 and mix for 15 min to obtain material 2.
  • Example 2 A method for preparing amisulpride tablets
  • the prescription information of the amisulpride tablets is shown in Table 2.
  • the preparation method is:
  • Coating The wet granules are placed in a fluidized bed and coated using a fluidized bed top spray process. All coating materials are sprayed in and dried until the loss on drying is less than 3%. Drying is then stopped.
  • Second mixing Add the other excipients in the prescription except magnesium stearate to material 1 and mix for 15 min to obtain material 2.
  • Example 3 A method for preparing amisulpride tablets
  • the prescription information of the amisulpride tablets is shown in Table 3.
  • the preparation method is:
  • Coating The wet granules are placed in a fluidized bed and coated using a fluidized bed top spray process. All coating materials are sprayed in and dried until the loss on drying is less than 3%. Drying is then stopped.
  • Second mixing Add the other excipients in the prescription except magnesium stearate to material 1 and mix for 15 min to obtain material 2.
  • Comparative Example 1 A method for preparing amisulpride tablets
  • Coating The wet granules are placed in a fluidized bed and coated using a fluidized bed top spray process. All coating materials are sprayed in and dried until the loss on drying is less than 3%. Drying is then stopped.
  • Example 2 The difference between this comparative example and Example 1 is that the prescription information of the amisulpride tablets is shown in Table 4, and the tablet hardness of the amisulpride tablets prepared therefrom is 36N.
  • Example 1 The difference between this comparative example and Example 1 is that the prescription information of the amisulpride tablets is shown in Table 5.
  • the tablet hardness of the prepared amisulpride tablets is 72N.
  • the present invention coats amisulpride with a coating material, and then selects a hydrophilic lubricant to mix with the coated particles, which effectively solves the sticking problem of amisulpride during tableting, as shown in A in Figure 1.
  • the hardness of the amisulpride tablets prepared by the present invention is relatively high, between 50-80N.
  • Comparative Example 1 changed the preparation method. Amisulpride was coated with a coating material and then mixed with other excipients not containing a hydrophobic lubricant. The hardness of the prepared tablets was as high as 78N. However, the amisulpride still had obvious sticking problems during the tableting process, as shown in B in Figure 1.
  • Comparative Examples 2 and 3 changed the dosage of coating materials, hydrophilic lubricants and hydrophobic lubricants, and the prepared amisulpride did not have the problem of sticking during the tableting process, but the hardness of the tablets prepared in Comparative Example 2 was relatively low.
  • the dissolution test results of the amisulpride tablets obtained by the preparation method of the present invention are consistent with those of the reference preparation, and can be dissolved very quickly, that is, the newly added prescription and process will not affect the release of the product.
  • the results are as follows:
  • the medium is hydrochloric acid, the temperature for dissolution determination is 37 ⁇ 0.5°C, and the rotation speed is 50 rpm.
  • the medium is acetate buffer, the temperature for dissolution determination is 37 ⁇ 0.5°C, and the rotation speed is 50 rpm.
  • the medium is phosphate buffer, the temperature for dissolution determination is 37 ⁇ 0.5°C, and the rotation speed is 50 rpm.

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Abstract

一种氨磺必利片的制备方法，属于医药制备技术领域，主要包括以下步骤：通过包衣材料对氨磺必利进行包衣处理，再选择亲水性润滑剂与包衣后的颗粒进行混合。针对氨磺必利自身性质导致的粘冲问题，提供了全新的解决措施，通过高分子包衣材料对氨磺必利进行包衣处理，再选择亲水性好的润滑剂与包衣后的颗粒进行混合，该方法不仅解决了氨磺必利易粘冲的问题，同时，制备的氨磺必利片的硬度高，溶出度好。

Description

一种氨磺必利片的制备方法
本发明要求于2022年11月18日提交中国专利局、申请号为202211443501.8、发明名称为“一种氨磺必利片的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在申请中。
技术领域
本发明涉及医药制备技术领域，具体来说，涉及一种氨磺必利片的制备方法。
背景技术
氨磺必利是一种非典型的抗精神病药物，主要用于精神病的治疗，具体用于类偏执狂进行性精神分裂症，急性妄谵型精神病的治疗，也可用于治疗精神分裂症的缺陷状态，残余的精神病演变以及伴有迟钝的抑制状态，还可用于治疗突出性原发消极症状以及精神抑郁症。
压片为口服固体制剂片剂生产过程中必不可少的工艺步骤。目前氨磺必利片片剂的生产中，其压片过程很容易出现粘冲的现象，发生粘冲后会影响素片的性状，严重更可能影响偏重差异导致含量和含量均匀度不合格。
面对发生粘冲的现象，目前常规的解决措施是：
(1)改变润滑剂用量和型号：增加硬脂酸镁等润滑剂用量和改变硬脂酸镁型号等方法。但是添加润滑剂用量后会导致片剂硬度偏低，崩解时间变慢。并且还有可能影响产品的稳定性和产品的溶出曲线。
(2)模具镀膜处理：模具镀膜后可能会对粘冲的问题得到改善。但镀膜所用的材料如特氟龙、铬等，价格较高。并且在生产过程中可能会产生涂层脱落或者磨损的风险，降低了药物的安全性。
(3)环境控制：如果压片过程中环境湿度过大，也会导致粘冲，因此也可以通过环境控制解决粘冲的问题。但大部分粘冲需要将环境湿度控制在35％RH以下，对生产车间的空调系统要求很高，并且增加了能耗。
(4)水分和粒度分布：总混颗粒的性质也可能会导致粘冲的发生，比如粒度分布和水分等。但该原因只能是大部分项目的控制手段，如部分原料药自身性质导致的粘冲则不会有任何改善。
CN111728947A公开了一种氨磺必利片及其制备方法，该氨磺必利片的组分包括氨磺必利、粘合剂、填充剂、崩解剂、润滑剂及辅助润滑剂，该发明利用热熔法制备氨磺必利片时意外的发现加入辅助润滑剂，解决了粘冲问题，该发明制备的氨磺必利片在pH为6.8时的溶出度较好，但其硬度偏低，会导致产品在包装和运输过程中发生碎片，影响产品质量。
CN112535671A公开了一种氨磺必利分散片及其制备方法，将活性药物氨磺必利与相应辅料混合均匀，采用湿法制粒工艺制成颗粒，其后采用流化床进行颗粒包衣，进而与其他辅料混合，压片制成分散片。该发明解决氨磺必利压片过程中出现的粘冲问题，但其片剂的硬度偏低，且溶出度受到了影响。
现有氨磺必利片的生产中为了改善压片过程中的粘冲问题，添加了辅助润滑剂或辅料，虽然解决粘冲的问题，但导致制备的片剂不同程度上存在硬度偏低、影响溶出度等问题。
发明内容
为了解决上述技术问题，本发明提供了一种氨磺必利片的制备方法，解决了氨磺比利易发生粘冲的问题，同时，制备的氨磺必利片的硬度高，溶出度好。
为了实现上述目的，本发明采用以下技术方案：
一种氨磺必利片的制备方法，包括以下步骤：通过包衣材料对氨磺必利进行包衣处理，再选择亲水性润滑剂与包衣后的颗粒进行混合。
优选地，所述包衣材料为海藻酸钠、聚维酮、离子交换树脂、乙基纤维素、醋酸纤维素、羟丙基纤维素中的至少两种；进一步优选为乙基纤维素和羟丙基纤维素；更进一步优选地，所述乙基纤维素和羟丙基纤维素的质量比为1:1。
进一步优选地，所述包衣材料的用量为氨磺必利片重量的1-3％。
优选地，所述亲水性润滑剂为硬质富马酸钠、滑石粉、十二烷基硫酸钠、微粉硅胶、聚乙二醇中的至少一种；最优选为硬质富马酸钠。
进一步优选地，所述亲水性润滑剂的用量为氨磺必利片重量的0.5-1.5％。
优选地，所述氨磺必利在包衣处理前，还包括利用包衣材料对氨磺必利进行湿法制粒，得到湿粒。
优选地，所述氨磺必利片的制备方法，具体包括以下步骤：
S1、湿法制粒：利用包衣材料对氨磺必利进行湿法制粒，得到湿粒；
S2、包衣：将步骤S1得到的湿粒进行包衣，干燥，整粒，得到包衣粒；
S3、第一次混合：将步骤S2得到的包衣粒与亲水性润滑剂混合，得到物料1；
S3、第二次混合：向步骤S3得到的物料1中加入辅料混合，得到物料2；
S4、总混：将步骤S3得到的物料2与疏水性润滑剂混合，得到总混料；
S5、压片：将步骤S4得到的总混料进行压片，得到所述氨磺必利片。
优选地，步骤S1中所述包衣材料的用量总包衣材料质量的20-30％。
优选地，步骤S3中所述辅料不含润滑剂。
进一步优选地，所述辅料包括崩解剂、填充剂、甜味剂和矫味剂中的至少一种。
优选地，步骤S4中所述疏水性润滑剂占氨磺必利片重量的0.5-1.5％。
进一步优选地，所述疏水性润滑剂为硬脂酸镁、硬质酸钙、甘油单硬脂酸酯和硬脂酸中的至少一种；最优选为硬脂酸镁。
优选地，步骤S5中所述氨磺必利片的硬度为50-80N。
本发明的有益效果为：
本发明针对氨磺必利自身性质导致的粘冲问题，提供了全新的解决措施，通过高分子包衣材料对氨磺必利进行包衣处理，再选择亲水性好的润滑剂与包衣后的颗粒进行混合，该方法不仅解决了氨磺必利易粘冲的问题，同时，制备的氨磺必利片的硬度高，溶出度好。
附图说明
图1为氨磺必利压片过程中的粘冲图，其中，A为本发明中实施例1压片过程中的粘冲图；B为本发明中对比例1压片过程中的粘冲图。
具体实施方式
以下实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对所公开的实施例的下述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例中，而是可以应用于符合与本文所公开的原理和新颖特点相一致的更宽的范围。虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料，本文在此处列举优选的方法和材料。
除非另外定义，本文中使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同意义。
实施例1一种氨磺必利片的制备方法
所述氨磺必利片的处方信息如表1所示。
表1氨磺必利片的处方用量

所述制备方法为：
(1)包衣材料的配制：先包衣材料使用95％的乙醇，配置成浓度为5％的包衣材料；
(2)湿法制粒：将处方量的氨磺必利置于湿法制粒机内，取1/4的包衣材料喷雾加入，对原料药进行湿法制粒，得到湿粒。
(3)包衣：将湿粒，放入流化床内，使用流化床顶喷工艺进行包衣，将全部包衣材料喷入，并干燥至干燥失重小于3％后停止干燥。
(4)整粒：包衣完成后使用快速整粒机将包衣后的物料过1.0mm网板，得到包衣粒。
(5)第一次混合：将处方量的硬质富马酸钠加入包衣粒中，进行混合，混合时间为10min，得到物料1。
(6)第二次混合：将处方中除硬脂酸镁以外的其他辅料加入到物料1中，进行混合，混合时间为15min，得到物料2。
(7)总混：将处方量的硬脂酸镁加入物料2中进行混合，混合时间为5min，得到总混料。
(8)压片：对总混料进行压片，得到片剂硬度为80N。
实施例2一种氨磺必利片的制备方法
所述氨磺必利片的处方信息如表2所示。
表2氨磺必利片的处方用量

所述制备方法为：
(1)包衣材料的配制：先包衣材料使用95％的乙醇，配置成浓度为5％的包衣材料；
(2)湿法制粒：将处方量的氨磺必利置于湿法制粒机内，取1/5的包衣材料喷雾加入，对原料药进行湿法制粒，得到湿粒。
(3)包衣：将湿粒，放入流化床内，使用流化床顶喷工艺进行包衣，将全部包衣材料喷入，并干燥至干燥失重小于3％后停止干燥。
(4)整粒：包衣完成后使用快速整粒机将包衣后的物料过1.0mm网板，得到包衣粒。
(5)第一次混合：将处方量的硬质富马酸钠加入包衣粒中，进行混合，混合时间为10min，得到物料1。
(6)第二次混合：将处方中除硬脂酸镁以外的其他辅料加入到物料1中，进行混合，混合时间为15min，得到物料2。
(7)总混：将处方量的硬脂酸镁加入物料2中进行混合，混合时间为5min，得到总混料。
(8)压片：对总混料进行压片，得到片剂硬度为52N。
实施例3一种氨磺必利片的制备方法
所述氨磺必利片的处方信息如表3所示。
表3氨磺必利片的处方用量
所述制备方法为：
(1)包衣材料的配制：先包衣材料使用95％的乙醇，配置成浓度为5％的包衣材料；
(2)湿法制粒：将处方量的氨磺必利置于湿法制粒机内，取3/10的包衣材料喷雾加入，对原料药进行湿法制粒，得到湿粒。
(3)包衣：将湿粒，放入流化床内，使用流化床顶喷工艺进行包衣，将全部包衣材料喷入，并干燥至干燥失重小于3％后停止干燥。
(4)整粒：包衣完成后使用快速整粒机将包衣后的物料过1.0mm网板，得到包衣粒。
(5)第一次混合：将处方量的硬质富马酸钠加入包衣粒中，进行混合，混合时间为10min，得到物料1。
(6)第二次混合：将处方中除硬脂酸镁以外的其他辅料加入到物料1中，进行混合，混合时间为15min，得到物料2。
(7)总混：将处方量的硬脂酸镁加入物料2中进行混合，混合时间为5min，得到总混料。
(8)压片：对总混料进行压片，得到片剂硬度为66N。
对比例1一种氨磺必利片的制备方法
本对比例与实施例1的区别在于，所述制备方法为：
(1)包衣材料的配制：先包衣材料使用95％的乙醇，配置成浓度为5％的包衣材料；
(2)湿法制粒：将处方量的氨磺必利置于湿法制粒机内，取包衣材料喷雾加入，对原料药进行湿法制粒，得到湿粒。
(3)包衣：将湿粒，放入流化床内，使用流化床顶喷工艺进行包衣，将全部包衣材料喷入，并干燥至干燥失重小于3％后停止干燥。
(4)整粒：包衣完成后使用快速整粒机将包衣后的物料过1.0mm网板，得到包衣粒。
(5)混合：将处方中除硬脂酸镁以外的其他辅料和包衣粒混合，混合时间为30min，得到物料。
(7)总混：将处方量的硬脂酸镁加入物料中进行混合，混合时间为5min，得到总混料。
(8)压片：对总混料进行压片，得到片剂硬度为78N。
对比例2一种氨磺必利片的制备方法
本对比例与实施例1的区别在于，所述氨磺必利片的处方信息如表4所示，其制备的氨磺必利片的片剂硬度为36N。
表4氨磺必利片的处方用量

对比例3一种氨磺必利片的制备方法
本对比例与实施例1的区别在于，所述氨磺必利片的处方信息如表5所示。其制备的氨磺必利片的片剂硬度为72N。
表5氨磺必利片的处方用量
一、粘冲及硬度
表6实施例及对比例的防粘冲及片剂硬度情况
由表6可知，本发明通过包衣材料对氨磺必利进行包衣处理，再选择亲水性润滑剂与包衣后的颗粒进行混合，有效解决了氨磺必利在压片过程中的粘冲问题，如图1中的A所示。同时由实施例1-3可知，本发明制备的氨磺必利片的硬度较高，在50-80N之间。
相比实施例1，对比例1改变了制备方法，利用包衣材料对氨磺必利进行包衣处理后，再与其他不含疏水性润滑剂的辅料混合，其制备的片剂的硬度较高为78N，但其氨磺必利在压片过程中仍存在明显的粘冲问题，如图1中的B所示。
对比例2和3改变了包衣材料、亲水性润滑剂和疏水性润滑剂的用量，其制备的氨磺必利在压片过程中不发生粘冲问题，但对比例2其制备的片剂的硬度较低。
二、溶出度检测
使用本发明的制备方法得到的氨磺必利片的溶出度检测结果均与参比制剂一致，可非常快速溶出，即新增加的处方和工艺不会对产品的释放产生影响。结果如下：
pH1.0介质溶出度检测结果，如表7所示。
表7 pH1.0介质溶出度检测结果
其中，介质为盐酸，溶出度测定的温度为：37±0.5℃，转速为50rpm。
pH4.5介质溶出度检测结果，如表8所示。
表8 pH4.5介质溶出度检测结果

其中，介质为醋酸盐缓冲液，溶出度测定的温度为：37±0.5℃，转速为50rpm。
pH6.8介质溶出度检测结果，如表9所示。
表9 pH6.8介质溶出度检测结果
其中，介质为磷酸盐缓冲液，溶出度测定的温度为：37±0.5℃，转速为50rpm。
以上是结合具体实施例对本发明进一步的描述，但这些实施例仅仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。

Claims (10)

  1. 一种氨磺必利片的制备方法，其特征在于，包括以下步骤：通过包衣材料对氨磺必利进行包衣处理，再选择亲水性润滑剂与包衣后的颗粒进行混合。
  2. 根据权利要求1所述的制备方法，其特征在于，所述包衣材料为乙基纤维素和羟丙基纤维素。
  3. 根据权利要求2所述的制备方法，其特征在于，所述包衣材料的用量为氨磺必利片重量的1-3％。
  4. 根据权利要求1所述的制备方法，其特征在于，所述亲水性润滑剂为硬质富马酸钠。
  5. 根据权利要求4所述的制备方法，其特征在于，所述亲水性润滑剂的用量为氨磺必利片重量的0.5-1.5％。
  6. 根据权利要求1所述的制备方法，其特征在于，所述氨磺必利在包衣处理前，还包括利用部分包衣材料对氨磺必利进行湿法制粒，得到湿粒。
  7. 根据权利要求1-6任一项所述的制备方法，其特征在于，具体包括以下步骤：
    S1、制粒：利用包衣材料对氨磺必利进行湿法制粒，得到湿粒；
    S2、包衣：将步骤S1得到的湿粒进行包衣，干燥，整粒，得到包衣粒；
    S3、第一次混合：将步骤S2得到的包衣粒与亲水性润滑剂混合，得到物料1；
    S3、第二次混合：向步骤S3得到的物料1中加入辅料混合，得到物料2；
    S4、总混：将步骤S3得到的物料2与疏水性润滑剂混合，得到总混料；
    S5、压片：将步骤S4得到的总混料进行压片，得到所述氨磺必利片。
  8. 根据权利要求7所述的制备方法，其特征在于，步骤S1中所述包衣材料为总包衣材料质量的20-30％。
  9. 根据权利要求8所述的制备方法，其特征在于，步骤S3中所述辅料包括崩解剂、填充剂、甜味剂和矫味剂中的至少一种，且不含润滑剂。
  10. 根据权利要求7所述的制备方法，其特征在于，所述疏水性润滑剂为硬脂酸镁。
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