WO2023040075A1 - 一种稳定的头孢克肟片剂及其制备方法 - Google Patents

一种稳定的头孢克肟片剂及其制备方法 Download PDF

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WO2023040075A1
WO2023040075A1 PCT/CN2021/136038 CN2021136038W WO2023040075A1 WO 2023040075 A1 WO2023040075 A1 WO 2023040075A1 CN 2021136038 W CN2021136038 W CN 2021136038W WO 2023040075 A1 WO2023040075 A1 WO 2023040075A1
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cefixime
tablet
stable
present
tablets
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PCT/CN2021/136038
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English (en)
French (fr)
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江荣高
潘锡明
罗嘉宾
张丽杰
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海南鑫开源医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, in particular to a stable cefixime tablet and a preparation method thereof.
  • Cefixime trihydrate (6R, 7R) ⁇ 7 ⁇ [(Z) ⁇ 2 ⁇ (2 ⁇ amino ⁇ 4 ⁇ thiazolyl) ⁇ 2 ⁇ (carboxymethoxyimino) acetamido] ⁇ 8 ⁇ oxo ⁇ 3 ⁇ ethylene ⁇ 5 ⁇ thia ⁇ 1 ⁇ azabicyclo[4.2.0]octene ⁇ 2 ⁇ ene ⁇ 2 ⁇ carboxylic acid trihydrate, the molecular formula is C 16 H 15 N 5 O 7 S 2 ⁇ 3H 2 O , the molecular weight is 507.50.
  • the chemical structural formula of cefixime is as follows:
  • cefixime The three waters of crystallization contained in cefixime are of great significance to its chemical stability. Therefore, in the process of formulation molding, it is necessary to prevent the loss of water of crystallization to maintain the chemical stability of cefixime trihydrate.
  • Cefixime tablets currently on the market in China are basically prepared by powder direct compression process or wet granulation process: (1) Powder direct compression process needs to control the particle size of the raw material drug within a wide range to solve the fluidity problem of the material , and avoid material stratification during the tableting process.
  • the crystalline structure of cefixime is easily damaged during the tableting process of the powder direct compression process, which is not conducive to its chemical stability; and the powder direct compression is also prone to sticking phenomenon, which leads to the tableting process is not smooth or needs to strictly control the humidity, resulting in The tablet production process is not smooth; (2) wet granulation process, which is more unfavorable for the production of cefixime tablets, because the ⁇ -lactam ring on the structure of cefixime is easily hydrolyzed under high temperature and high humidity conditions Ring opening leads to oxidation or degradation of cefixime, and the stability of the preparation product is poor, which is not conducive to long-term storage.
  • the object of the invention is to provide a kind of stable cefixime tablet and preparation method thereof, the cefixime tablet prepared by the method provided by the invention has better Stability, and due to the use of small particle size raw materials, drug release is also faster.
  • the invention provides a kind of preparation method of stable cefixime tablet, comprising:
  • the particle diameter d 90 of the cefixime bulk drug is 20 ⁇ m to 90 ⁇ m.
  • the auxiliary materials include: fillers, glidants and lubricants.
  • the mass content of the cefixime bulk drug in the stable cefixime tablet is 10%-70%; the mass content of the binder in the stable cefixime tablet is 0.3%- 1.5%; the mass content of the filler in the stable cefixime tablet is 25% to 85%; the mass content of the glidant in the stable cefixime tablet is 0.5% to 5.0%; The mass content of the lubricant in the stable cefixime tablet is 0.3%-4.0%.
  • the binder is at least one selected from methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, starch and gelatin.
  • the filler is at least one selected from microcrystalline cellulose, pregelatinized starch, lactose, sucrose and calcium hydrogen phosphate.
  • the glidant is selected from at least one of talc powder and colloidal silicon dioxide.
  • the lubricant is selected from at least one of magnesium stearate, calcium stearate, hydrogenated vegetable oil and polyethylene glycol.
  • the auxiliary material also includes: a disintegrant.
  • the disintegrant is at least one selected from sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone.
  • the invention provides a stable cefixime tablet prepared by the method described in the above technical scheme.
  • the preparation method of the stable cefixime tablet provided by the invention has stable product quality and good fluidity of materials in the production process, and solves the defects of tablet sticking and poor chemical stability of the product in the prior art.
  • Fig. 1 is the dissolution curve of the tablet prepared by the embodiment of the present invention 1 and embodiment 4;
  • Fig. 2 is the particle size distribution diagram of the cefixime bulk drug used in Example 2 of the present invention.
  • the invention provides a kind of preparation method of stable cefixime tablet, comprising:
  • cefixime bulk drug is wet-granulated with a binder, and the drug-containing granules are obtained after drying;
  • the particle diameter d 90 of the cefixime bulk drug is 20 ⁇ m to 90 ⁇ m.
  • the invention provides a kind of preparation method of stable cefixime tablet, preferably comprises:
  • the particle diameter d 90 of the cefixime bulk drug is 20 ⁇ m to 90 ⁇ m.
  • the composition of the cefixime bulk drug is cefixime trihydrate, namely (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2 -(carboxymethoxyimino)acetamido]-8-oxo-3-ethylene-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate,
  • the molecular formula is C 16 H 15 N 5 O 7 S 2 ⁇ 3H2O, and the molecular weight is 507.50.
  • the particle size d 90 of the cefixime bulk drug is 20 ⁇ m to 90 ⁇ m, preferably 20 ⁇ m to 50 ⁇ m, more preferably 30 ⁇ m to 40 ⁇ m.
  • the mass content of the cefixime bulk drug in the stable cefixime tablet is preferably 10%-70%, more preferably 20%-50%, more preferably 30%-50%.
  • the binder is preferably at least one selected from methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, starch and gelatin.
  • the mass content of the binder in the stable cefixime tablet is preferably 0.3%-1.5%, more preferably 0.5%-1.2%.
  • the method of granulation preferably includes:
  • cefixime bulk drug and the binder solution are mixed and granulated, dried and sized to obtain granules.
  • the binder solution is preferably an aqueous binder solution; the mass concentration of the binder solution is preferably 2%-14%, more preferably 5%-10%.
  • the granulation is preferably carried out in a high-efficiency wet granulator, and the cefixime bulk drug is placed in a high-efficiency wet granulator, atomized and sprayed into the binder solution under mixing and shearing for granulation.
  • the drying temperature is preferably 30°C-50°C, more preferably 35°C-45°C, most preferably 40°C; the drying method is preferably oven drying.
  • the sizing is preferably 30 mesh to 50 mesh, more preferably 35 mesh to 45 mesh, and most preferably 40 mesh.
  • the auxiliary materials preferably include fillers, glidants and lubricants.
  • the filler is preferably at least one selected from microcrystalline cellulose, pregelatinized starch, lactose, sucrose and calcium hydrogen phosphate; the fluidity of the filler meets the requirements of the powder direct compression process.
  • the mass content of the filler in the stable cefixime tablet is preferably 25%-85%, more preferably 30%-80%.
  • the glidant is preferably at least one selected from talc powder and colloidal silicon dioxide.
  • the mass content of the glidant in the stable cefixime tablet is preferably 0.5%-5.0%.
  • the lubricant is preferably at least one selected from magnesium stearate, calcium stearate, hydrogenated vegetable oil and polyethylene glycol.
  • the mass content of the lubricant in the stable cefixime tablet is preferably 0.3%-4.0%.
  • the auxiliary material preferably further includes: a disintegrant.
  • the disintegrant is preferably at least one selected from sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone.
  • the mass content of the disintegrant in the stable cefixime tablet is preferably 2%-8%, more preferably 3%-6%.
  • the tableting method is preferably rotary tableting; the rotation speed during the tableting process is preferably 10 rpm to 35 rpm.
  • the hardness of the compressed tablet is preferably controlled at 4kg ⁇ 7kg; when the specification of cefixime is 50mg/tablet, the hardness of the compressed tablet is preferably controlled at 3kg ⁇ 6kg.
  • the present invention also provides a stable cefixime tablet prepared by the method described in the above technical solution.
  • cefixime tablet provided by the invention is different from the traditional method.
  • cefixime is not suitable for wet granulation, because wet granulation is likely to cause the ⁇ -lactam ring on the structure of cefixime to be hydrolyzed and opened under high temperature and high humidity conditions, and cefixime will produce degradation products and gradually fail.
  • the method provided by the present invention is different from the traditional wet granulation process.
  • the traditional wet granulation process is to granulate the mixture after mixing the raw and auxiliary materials, dry, and finally mix and compress the tablet, while the present invention only wet-granulates the bulk drug, After drying, it is mixed with other excipients such as fillers and compressed into tablets.
  • cefixime tablets is mainly powder direct compression, that is, mixing the raw and auxiliary materials and then directly compressing the tablets.
  • the purpose is to avoid the moisture and drying and heating process in the wet granulation process, so as to ensure the chemical stability of cefixime .
  • cefixime tablet is easy to stick and rush, in order to ensure that the powder direct compression process can be carried out smoothly, it is usually necessary to control the relative humidity of the environment below 55%, and it is best to control the humidity Below 40%, the harsh tableting conditions are neither easy to achieve nor cause the tableting operator to reduce the physical comfort of the workers due to the low air humidity; Layering, which in turn affects the weight difference and content uniformity of the tablet; (3)
  • the powder direct compression process requires a large particle size of the raw material drug, and the crystalline structure of cefixime is easily damaged due to pressure during the compression process, which in turn leads to The chemical stability of cefixime in the prepared tablet becomes worse.
  • the invention uses a suitable binder to carry out wet granulation on the raw material, and then mixes it with other auxiliary materials and then compresses it into tablets.
  • the present invention not only solves the sticking problem of cefixime in tableting process, but also remarkably improves the chemical stability of cefixime, and improves the stability of the tablet because of the use of fine-grained raw materials. dissolution rate.
  • d 90 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%
  • d 50 refers to the corresponding particle size when the cumulative particle size distribution number of a sample reaches 50%
  • d 10 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 10%.
  • the particle diameters described in the embodiments of the present invention are all measured by a laser particle size analyzer.
  • the particle size of a sample measured by a laser particle size analyzer is divided into a wet method (the sample is dispersed in a suitable liquid medium) and a dry method (the sample is dispersed in a gas, keep dry state), the particle size in the embodiments of the present invention is all measured by dry method.
  • the dry granules are mixed with talcum powder and magnesium stearate and compressed into tablets (rotary compression with a rotation speed of 10rpm to 30rpm), the weight of the controlled tablet is 267mg, and the hardness is 4kg to 7kg to obtain tablets; the tablets are packed in blisters.
  • Example 1 Press the mixture into tablets (rotary tableting, with a rotational speed of 10rpm to 30rpm), and control the hardness to 4kg to 7kg.
  • the tablet weights of Example 1, Example 2, Example 3 and Example 4 are sequentially controlled to be about 266mg and 220mg , 233mg and 234mg to obtain tablets;
  • the tablets are blister packed.
  • Table 3 embodiment 1 ⁇ 4 prepares the prescription of tablet
  • cefixime is the bulk drug
  • hypromellose and hydroxypropyl cellulose are binders
  • microcrystalline cellulose lactose
  • pregelatinized starch and calcium hydrogen phosphate are fillers
  • sodium starch glycolate is 1.
  • Low-substituted hydroxypropyl cellulose is used as disintegrant
  • talc powder and colloidal silicon dioxide are used as glidants
  • magnesium stearate and hydrogenated vegetable oil are used as lubricants.
  • Example 1 The samples prepared in Example 1, Example 2, Example 3 and Example 4 were respectively placed at 40°C for 30 days, and samples were taken at 0 days, 5 days, 10 days and 30 days respectively to investigate their chemical stability , the results are shown in Table 4:
  • the present invention uses a suitable binder to carry out wet granulation of the raw material, and then mixes it with other auxiliary materials and then compresses it into tablets.
  • the present invention not only solves the sticking problem of cefixime in tableting process, but also remarkably improves the chemical stability of cefixime, and improves the stability of the tablet because of the use of fine-grained raw materials. dissolution rate.

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Abstract

本发明提供了一种稳定的头孢克肟片剂的制备方法，包括：将头孢克肟原料药湿法制粒、干燥，加入其他物料混合后压片，得到稳定的头孢克肟片剂；所述头孢克肟原料药的粒径d 90在20μm～90μm范围。本发明提供的方法制备得到的片剂可有效解决头孢克肟片剂压制过程中的粘冲问题、提高头孢克肟在制剂中化学稳定性和溶出速率。

Description

一种稳定的头孢克肟片剂及其制备方法
本申请要求于2021年9月18日提交中国专利局、申请号为202111119913.1、发明名称为“一种稳定的头孢克肟片剂及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物制剂技术领域，尤其涉及一种稳定的头孢克肟片剂及其制备方法。
背景技术
头孢克肟三水合物，(6R，7R)～7～[(Z)～2～(2～氨基～4～噻唑基)～2～(羧甲氧亚氨基)乙酰氨基]～8～氧代～3～乙烯～5～硫杂～1～氮杂双环[4.2.0]辛～2～烯～2～羧酸三水合物，分子式为C 16H 15N 5O 7S 2·3H 2O，分子量为507.50。头孢克肟的化学结构式如下：
Figure PCTCN2021136038-appb-000001
头孢克肟含有的三个结晶水对其化学稳定性具有重要意义，因此在制剂成型过程中，需要防止结晶水的丢失以维持头孢克肟三水合物的化学稳定性。
目前国内上市的头孢克肟片剂基本上采用粉末直压工艺或湿法制粒工艺制备：(1)粉末直压工艺，需要控制原料药的粒径在较大范围，以解决物料的流动性问题、并避免压片过程中的物料分层。粉末直压工艺压片过程中头孢克肟的晶型结构容易受到破坏，从而不利于其化学稳定性；且粉末直压还容易出现粘冲现象导致压片过程不顺利或需要严格控制湿度，导致片剂生产过程不顺畅；(2)湿法制粒工艺，该工艺更不利于头孢克肟片剂的生产，因为头孢克肟结构上的β～内酰胺环在高温、高湿的条件下易水解开环，导致头孢克肟产生氧化或者降解，且制剂产品的稳定性较差，不利于长期存放。
发明内容
有鉴于头孢克肟片剂现有生产工艺的局限性，本发明的目的在于提供一种稳定的头孢克肟片剂及其制备方法，本发明提供的方法制备的头孢克肟片剂具有较好的稳定性，且由于采用了小粒径的原料药，所以药物释放也更迅速。
本发明提供了一种稳定的头孢克肟片剂的制备方法，包括：
将头孢克肟原料药和粘合剂混合制粒，干燥后得到颗粒；
将所述颗粒和辅料混合后压制成片，得到稳定的头孢克肟片剂；
所述头孢克肟原料药的粒径d 90为20μm～90μm。
优选的，所述辅料包括：填充剂、助流剂和润滑剂。
优选的，所述头孢克肟原料药在稳定的头孢克肟片剂中的质量含量为10％～70％；所述粘合剂在稳定的头孢克肟片剂中的质量含量为0.3％～1.5％；所述填充剂在稳定的头孢克肟片剂中的质量含量为25％～85％；所述助流剂在稳定的头孢克肟片剂中的质量含量为0.5％～5.0％；所述润滑剂在稳定的头孢克肟片剂中的质量含量为0.3％～4.0％。
优选的，所述粘合剂选自甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、聚维酮、淀粉和明胶中的至少一种。
优选的，所述填充剂选自微晶纤维素、预胶化淀粉、乳糖、蔗糖和磷酸氢钙中的至少一种。
优选的，所述助流剂选自滑石粉和胶态二氧化硅中的至少一种。
优选的，所述润滑剂选自硬脂酸镁、硬脂酸钙、氢化植物油和聚乙二醇中的至少一种。
优选的，所述辅料还包括：崩解剂。
优选的，所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素和交联聚维酮中的至少一种。
本发明提供了一种上述技术方案所述的方法制备得到的稳定的头孢克肟片剂。
本发明提供的稳定的头孢克肟片剂的制备方法，产品质量稳定好，在生产过程中物料的流动性好，解决了现有技术中存在的压片粘冲、产品化学稳定性差的缺陷。
附图说明
图1为本发明实施例1和实施例4制备的片剂溶出曲线；
图2为本发明实施例2所采用的头孢克肟原料药的粒度分布图。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员经改进或润饰的所有其它实例，都属于本发明保护的范围。应理解，本发明实施例仅用于说明本发明的技术效果，而非用于限制本发明的保护范围。实施例中，所用方法如无特别说明，均为常规方法。
本发明提供了一种稳定的头孢克肟片剂的制备方法，包括：
将头孢克肟原料药以粘合剂湿法制粒，干燥后得到含药颗粒；
将所述含药颗粒和其他辅料混合后压制成片，得到稳定的头孢克肟片剂；
所述头孢克肟原料药的粒径d 90为20μm～90μm。
本发明提供了一种稳定的头孢克肟片剂的制备方法，优选包括：
将头孢克肟原料药和粘合剂混合制粒，得到颗粒；
将所述颗粒和辅料混合后压制成片，得到稳定的头孢克肟片剂；
所述头孢克肟原料药的粒径d 90为20μm～90μm。
在本发明中，所述头孢克肟原料药的成分为头孢克肟三水合物，即(6R，7R)-7-[(Z)-2-(2-氨基-4-噻唑基)-2-(羧甲氧亚氨基)乙酰氨基]-8-氧代-3-乙烯-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸三水合物，分子式为C 16H 15N 5O 7S 2·3H2O，分子量为507.50。
在本发明中，所述头孢克肟原料药的粒径d 90为20μm～90μm，优选为20μm～50μm，更优选为30μm～40μm。
在本发明中，所述头孢克肟原料药在稳定的头孢克肟片剂中的质量含量优选为10％～70％，更优选为20％～50％，更优选为30％～50％。
在本发明中，所述粘合剂优选选自选自甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、聚维酮、淀粉和明胶中的至少一种。
在本发明中，所述粘合剂在稳定的头孢克肟片剂中的质量含量优选为0.3％～1.5％，更优选为0.5％～1.2％。
在本发明中，所述制粒的方法优选包括：
将头孢克肟原料药和粘合剂溶液混合制粒，干燥，整粒，得到颗粒。
在本发明中，所述粘合剂溶液优选为粘合剂水溶液；所述粘合剂溶液的质量浓度优选为2％～14％，更优选为5％～10％。
在本发明中，所述制粒优选在高效湿法制粒机中进行，将头孢克肟原料药置于高效湿法制粒机中，混合剪切下雾化喷入粘合剂溶液进行制粒。
在本发明中，所述干燥的温度优选为30℃～50℃，更优选为35℃～45℃，最优选为40℃；所述干燥方式优选为烘箱烘干。
在本发明中，所述整粒优选为30目～50目整粒，更优选为35目～45目，最优选为40目。
在本发明中，所述辅料优选包括：填充剂、助流剂和润滑剂。
在本发明中，所述填充剂优选选自微晶纤维素、预胶化淀粉、乳糖、蔗糖和磷酸氢钙中的至少一种；所述填充剂的流动性满足粉末直压工艺的需要。
在本发明中，所述填充剂在稳定的头孢克肟片剂中的质量含量优选为25％～85％，更优选为30％～80％。
在本发明中，所述助流剂优选自滑石粉和胶态二氧化硅中的至少一种。
在本发明中，所述助流剂在稳定的头孢克肟片剂中的质量含量优选为0.5％～5.0％。
在本发明中，所述润滑剂优选选自硬脂酸镁、硬脂酸钙、氢化植物油和聚乙二醇中的至少一种。
在本发明中，所述润滑剂在稳定的头孢克肟片剂中的质量含量优选为0.3％～4.0％。
在本发明中，所述辅料优选还包括：崩解剂。
在本发明中，所述崩解剂优选选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素和交联聚维酮中的至少一种。
在本发明中，所述崩解剂在在稳定的头孢克肟片剂中的质量含量优选为2％～8％，更优选为3％～6％。
在本发明中，所述压片的方法优选为旋转压片；所述压片过程中的旋转速度优选为10rpm～35rpm。
在本发明中，所述压片过程中头孢克肟规格为0.1g/片时，压片的硬度优选控制在4kg～7kg；头孢克肟规格为50mg/片时，压片的硬度优选控制在3kg～6kg。
本发明还提供了一种上述技术方案所述的方法制备得到的稳定的头孢克肟片剂。
本发明提供的头孢克肟片的制备方法与传统方法不同。一般来说，头孢克肟不适于湿法制粒，因为湿法制粒容易造成头孢克肟结构上的β～内酰胺环在高温、高湿的条件下水解开环，头孢克肟产生降解产物而逐渐失效。但是本发明提供的方法与传统的湿法制粒工艺不同，传统的湿法制粒工艺是将原辅料混合后对混合物制粒、干燥、总混合压片，而本发明只将原料药湿法制粒、干燥、再与填充剂等其他辅料混合后压片。
另外，头孢克肟片当前的生产工艺主要是粉末直接压片，即将原辅料混合后直接压片，目的是避免湿法制粒过程中的水分和干燥受热过程，以保证头孢克肟的化学稳定性。但是，粉末直接压片工艺存在的缺点在于：(1)头孢克肟压片容易粘冲，为了保证粉末直接压片过程能够顺利进行，通常需要控制环境相对湿度在55％以下，最好控制湿度在40％以下，压片条件的严苛既不容易实现也令压片操作工因空气湿度过低导致劳动者体感舒适度降低；(2)粉末直接压片还容易导致片剂压制过程中粉末分层，进而影响片剂的重量差异和含量均匀度；(3)粉末直压工艺要求原料药粒径较大，压制过程中头孢克肟因为承压导致其晶型结构容易受到破坏，进而导致所制得片剂中头孢克肟的化学稳定性变差。
本发明在控制头孢克肟原料粒径的基础上，采用适宜的粘合剂对原料进行湿法制粒，然后再与其他辅料物料混合后压片。令人惊奇的是，本发明不仅解决了头孢克肟压片过程中粘冲的问题，还显著提高了头孢克肟的化学稳定性，同时也因为采用细粒径的原料药而提高了片剂的溶出速率。
下面将通过实施例对本发明进一步详细说明，但是需要注意的是，实施例仅仅是为了更好的理解本发明，而不能理解为对权利要求书的限制。
本发明可以有许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体地实施例的目的，不是旨在于限制本发明。
本文中的术语解释，“d 90”是指一个样品的累计粒度分布数达到90％时所对应的粒径，“d 50”是指一个样品的累计粒度分布数达到50％时所对应的粒径，“d 10”是指一个样品的累计粒度分布数达到10％时所对应的粒径。
本发明实施例中所述的粒径均是激光粒度仪测定而得，激光粒度仪测定样品的粒度分为湿法(样品分散于适当的液体介质中)和干法(样品分散于气体中，保持干燥状态)，本发明实施例中的粒度均是采用干法测得。
比较例1
按照表1中的原料及用量采用湿法制粒进行片剂制备：
将羟丙基纤维素溶于适量纯化水，制成浓度为7.4％(g/g)的水溶液作为粘合剂溶液；
将头孢克肟、微晶纤维素、无水乳糖、预胶化淀粉和羧甲淀粉钠置于高效湿法制粒机中，混合均匀，以上述粘合剂溶液雾化喷入制粒；
在40℃鼓风烘箱干燥；40目整粒，得到干颗粒；
将干颗粒混入滑石粉、硬脂酸镁混合压片(旋转压片，旋转速度为10rpm～30rpm)，控制片重为267mg，硬度为4kg～7kg，得到片剂；将片剂泡罩包装。
比较例2
按照表1中的原料及用量采用粉末直压工艺制备片剂：
将所有物料置于三维混合器中，混合均匀，得到混合物；
混入滑石粉、硬脂酸镁，压片，控制片重为267mg，硬度为4kg～7kg，得到片剂；将片剂泡罩包装。
表1比较例1和比较例2制备片剂的处方
Figure PCTCN2021136038-appb-000002
Figure PCTCN2021136038-appb-000003
将比较例1和比较例2所制得的样品置于40℃放置30天，分别于0天、5天、10天和30天取样，考察其化学稳定性，采用HPLC法测定杂质含量，结果如表2：
表2比较例1和比较例2制备片剂的化学稳定性
Figure PCTCN2021136038-appb-000004
结果表明，虽然粉末直接压片工艺比湿法制粒工艺压片工艺可获取更好的化学稳定性，但是杂质控制仍然不够理想；而且压片过程中也存在片重差异较大和粘冲现象。
实施例1～4
按照表3中的原料成分及用量制备片剂：
将羟丙甲纤维素或羟丙基纤维素溶于适量纯化水，制成浓度为7.41％(g/g)的粘合剂；
将头孢克肟置于高效湿法制粒机中，混合剪切下雾化喷入粘合剂进行制粒；
40℃鼓风烘箱干燥；40目筛网整粒，得到颗粒；
将物料置于三维混合器中，加入剩余物料混匀，得到混合物；
将所述混合物压片(旋转压片，转速为10rpm～30rpm)，控制硬度为4kg～7kg，实施例1、实施例2、实施例3和实施例4的片重依次控制为约266mg、220mg、233mg和234mg，得到片剂；
将所述片剂泡罩包装。
表3实施例1～4制备片剂的处方
Figure PCTCN2021136038-appb-000005
表3中，头孢克肟为原料药，羟丙甲纤维素、羟丙基纤维素为粘合剂，微晶纤维素、乳糖、预胶化淀粉和磷酸氢钙为填充剂，羧甲淀粉钠、低取代羟丙基纤维素为崩解剂，滑石粉、胶态二氧化硅为助流剂，硬脂酸镁、氢化植物油为润滑剂。
将实施例1、实施例2、实施例3和实施例4所制得的样品分别置于40℃放置30天，分别于0天、5天、10天和30天取样，考察其化学稳定性，结果如表4：
表4实施例1～4制备片剂的化学稳定性
Figure PCTCN2021136038-appb-000006
结果表明，仅对原料药进行湿法制粒工艺压片(本发明提供的方法)可获取更好的化学稳定性，并且随着原料药粒径的降低，片剂的化学稳定性逐步提高；而且原料药经过湿法制粒，改善了压片过程中的粘冲现象，同时降低了片重差异。
以pH1.2的盐酸溶液为溶出介质，采用桨法测定实施例1和实施例4的溶出曲线，检测结果如图1所示，表明原料药粒径越小，溶出越快。
由以上实施例可知，本发明在控制头孢克肟原料粒径的基础上，采用适宜的粘合剂对原料进行湿法制粒，然后再与其他辅料物料混合后压片。令人惊奇的是，本发明不仅解决了头孢克肟压片过程中粘冲的问题，还显著提高了头孢克肟的化学稳定性，同时也因为采用细粒径的原料药而提高了片剂的溶出速率。
虽然已参考本发明的特定实施例描述并说明本发明，但是这些描述和说明并不限制本发明。所属领域的技术人员可清晰地理解，在不脱离如由所附权利要求书定义的本发明的真实精神和范围的情况下，可进行各种改变，以使特定情形、材料、物质组成、物质、方法或过程适宜于本申请的目标、精神和范围。所有此类修改都意图在此所附权利要求书的范围内。虽然已参考按特定次序执行的特定操作描述本文中所公开的方法，但应理解，可在不脱离本发明的教示的情况下组合、细分或重新排序这些操作以形成等效方法。因此，除非本文中特别指示，否则操作的次序和分组并非本申请的限制。
以上所述仅是本发明的优选实施方式，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，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (9)

  1. 一种稳定的头孢克肟片剂的制备方法，包括：
    将头孢克肟原料药以粘合剂湿法制粒，干燥后得到含药颗粒；
    将所述含药颗粒和其他辅料混合后压制成片，得到稳定的头孢克肟片剂；
    所述头孢克肟原料药的粒径d 90为20μm～90μm。
  2. 根据权利要求1所述的方法，其特征在于，所述辅料包括：填充剂、助流剂和润滑剂。
  3. 根据权利要求1所述的方法，其特征在于，所述粘合剂选自甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、聚维酮、淀粉和明胶中的至少一种。
  4. 根据权利要求2所述的方法，其特征在于，所述填充剂选自微晶纤维素、预胶化淀粉、乳糖、蔗糖和磷酸氢钙中的至少一种。
  5. 根据权利要求2所述的方法，其特征在于，所述助流剂选自滑石粉和胶态二氧化硅中的至少一种。
  6. 根据权利要求2所述的方法，其特征在于，所述润滑剂选自硬脂酸镁、硬脂酸钙、氢化植物油和聚乙二醇中的至少一种。
  7. 根据权利要求2所述的方法，其特征在于，所述辅料还包括：崩解剂。
  8. 根据权利要求7所述的方法，其特征在于，所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素和交联聚维酮中的至少一种。
  9. 一种权利要求1所述的方法制备得到的稳定的头孢克肟片剂。
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