WO2022205576A1 - 一种头孢拉定胶囊的制备方法 - Google Patents

一种头孢拉定胶囊的制备方法 Download PDF

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WO2022205576A1
WO2022205576A1 PCT/CN2021/093546 CN2021093546W WO2022205576A1 WO 2022205576 A1 WO2022205576 A1 WO 2022205576A1 CN 2021093546 W CN2021093546 W CN 2021093546W WO 2022205576 A1 WO2022205576 A1 WO 2022205576A1
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cefradine
preparation
dissolution
cellulose
raw material
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English (en)
French (fr)
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许丹青
余国新
耿亮
朱亚东
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海南海力制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a preparation method of cefradine capsules.
  • Cephradine (Cephradine, Velosef), also known as cephalosporin VI, cephalosporin VI, etc., is the first-generation semi-synthetic cephalosporin, and its antibacterial effect is similar to that of cephalexin.
  • This product is acid-resistant and can be taken orally, with good absorption and high blood concentration. It is characterized by resistance to ⁇ -lactamase, and has rapid and reliable bactericidal effect on drug-resistant Staphylococcus aureus and other bacilli that are resistant to broad-spectrum antibiotics. , mainly excreted in the original form through the urine, and the concentration in the urine is higher. Clinically, it is mainly used for infections of the respiratory tract, urinary tract, skin and soft tissues, such as bronchitis, pneumonia, pyelonephritis, cystitis, ENT infection, enteritis and dysentery.
  • cefradine is a ⁇ -lactam antibiotic, its chemical properties are unstable, it is easy to hydrolyze, and it is sensitive to high temperature, so it is not suitable to use wet granulation. The possibility of the drug is low, and the dissolution rate and bioavailability of the drug are not high.
  • the object of the present invention is to provide a preparation method of cefradine capsules in view of the deficiencies of the prior art, changing from the original direct mixing to dry granulation, to obtain granules with better fluidity, so that the dissolution rate of the product is improved, and the concentration of the drug is increased.
  • Bioavailability, with the addition of lubricants, ensures product stability and the possibility of continuous production.
  • a preparation method of cefradine capsule comprising the following steps:
  • S1 preparation of raw materials and auxiliary materials: pulverize the raw material cefradine and pass it through a screen to obtain the raw material cefradine that meets the particle size requirements; then pass the filler, disintegrant, binder and lubricant through the first mesh screen respectively, Obtain fillers, disintegrants, binders and lubricants that meet the particle size requirements;
  • batch mixing add the above particles and lubricant into a three-dimensional motion mixer with a frequency of 10Hz, and mix for 8-12min;
  • capsule filling put the above mixed granules into a capsule filling machine for capsule filling to obtain cefradine capsules.
  • the disintegrant includes one of crospovidone, sodium carboxymethyl starch, croscarmellose sodium or low-substituted hydroxypropyl cellulose sodium.
  • the filler includes one of microcrystalline cellulose, a combination of microcrystalline cellulose and calcium hydrogen phosphate, or a combination of microcrystalline cellulose and starch.
  • the lubricant includes one of magnesium stearate, calcium stearate, stearic acid or talc.
  • the binder includes one of sodium carboxymethyl cellulose, methyl cellulose or hydroxypropyl cellulose.
  • the raw material cefradine is pulverized and sieved to obtain the raw material cefradine that meets the particle size requirements.
  • the particle size of the raw material cefradine that meets the particle size requirements is less than 120 microns.
  • the first mesh number is 30-70.
  • the second mesh number is 15-25.
  • the present invention mainly overcomes the shortcoming that the poor fluidity of the materials in the direct mixing process is not conducive to continuous production; the present invention adopts the dry granulation process to obtain particles with better fluidity, and adds a lubricant to ensure product stability and the possibility of continuous production sex.
  • the process is simple, saving a lot of manpower and material resources.
  • the samples prepared by the process of the present invention have high particle fluidity, and the dissolution limit can be greater than 90%, which ensures the rapid dissolution and biological efficacy of cefradine capsules, and improves the bioavailability of the drug.
  • a preparation method of cefradine capsules comprises the steps of dry granulation and capsule filling after mixing cefradine with pharmaceutical excipients.
  • pharmaceutical adjuvants include one or more of disintegrants, fillers, lubricants, and adhesives.
  • the disintegrating agent includes one of crospovidone, sodium carboxymethyl starch, croscarmellose sodium or low-substituted hydroxypropyl cellulose sodium, wherein, preferably sodium carboxymethyl starch , Croscarmellose sodium, most preferably sodium carboxymethyl starch.
  • the filler includes one of microcrystalline cellulose, a combination of microcrystalline cellulose and calcium hydrogen phosphate, or a combination of microcrystalline cellulose and starch, among which, microcrystalline cellulose is the most preferred.
  • the lubricant includes one of magnesium stearate, calcium stearate, stearic acid or talc, wherein preferably magnesium stearate and talc, and most preferably magnesium stearate.
  • the binder includes a kind of sodium carboxymethyl cellulose, methyl cellulose or hydroxypropyl cellulose, wherein, preferably sodium carboxymethyl cellulose, hydroxypropyl cellulose, most preferably carboxymethyl cellulose sodium.
  • the most preferred prescription composition is:
  • S1 preparation of raw materials and auxiliary materials: pulverize the raw material cefradine and pass it through a screen to obtain the raw material cefradine that meets the particle size requirements; then pass the filler, disintegrant, binder and lubricant through the first mesh screen respectively, Obtain fillers, disintegrants, binders and lubricants that meet the particle size requirements;
  • batch mixing add the above particles and lubricant into a three-dimensional motion mixer with a frequency of 10Hz, and mix for 8-12min, preferably for 10min;
  • capsule filling put the above mixed granules into a capsule filling machine for capsule filling to obtain cefradine capsules.
  • step S1 the raw material cefradine is pulverized and sieved to obtain the raw material cefradine that meets the particle size requirements. is less than 40 microns.
  • the first mesh number is 30-70, which can be selected according to the particle size of the required particles, and is preferably 50.
  • the second mesh number is 15-25, which can be selected according to the particle size of the required particles, and is preferably 20.
  • the parameters of the dry granulator are the stirring speed of 25rpm, the screw speed of 55-85rpm, the roller speed of 16rpm, the gap of the rollers of 0.9-1.3mm, the granulation speed of 80rpm, the pressure of the rollers of 70bar, the sieve diameter of 1.0mm, Vacuum degree 0.1bar.
  • the present invention mainly overcomes the shortcoming that the poor fluidity of the material in the direct mixing process is not conducive to continuous production; the present invention adopts the dry granulation process to obtain particles with better fluidity, and with the addition of a lubricant, the product stability and the possibility of continuous production can be ensured;
  • the process of the invention is simple and saves a lot of manpower and material resources; the samples prepared by the process of the invention have high particle fluidity, ensure the rapid dissolution of cefradine capsules and biological efficacy, and improve the bioavailability of the drug.
  • the most preferred formulation composition is:
  • S1 preparation of raw materials and auxiliary materials: pulverize the raw material cefradine and pass through a screen to obtain cefradine with a particle size of 25-35 microns; then separate microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and stearin. Magnesium acid is passed through a 50-mesh sieve to obtain microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and magnesium stearate that meet the particle size requirements;
  • capsule filling put the above mixed granules into a capsule filling machine for capsule filling to obtain cefradine capsules.
  • the dissolution test method (Second method of Appendix X C of Chinese Pharmacopoeia 2010 Edition), take 900ml of water as the solvent, the rotation speed is 100 revolutions per minute, operate according to the law, after 5, 10, 15, 30, 45, 60 minutes respectively Take an appropriate amount of the solution, filter it, and take the subsequent filtrate as the test solution.
  • accurately weigh 5 mg of cefradine reference substance put it in a 50 ml volumetric flask, dissolve and dilute to the mark with acetonitrile-water (70:30), shake well, accurately measure an appropriate amount, and dilute with water to form a solution containing 5 ⁇ g of cefradine per 1 ml.
  • the dissolution amount at different time points was calculated, and the measurement data of the dissolution curve are shown in Table 1.
  • dissolution test method (Second method of Appendix X C of Chinese Pharmacopoeia 2010 Edition), take 900ml of hydrochloric acid solution with pH of 1.2 as solvent, rotate speed at 100 revolutions per minute, operate according to law, and pass 5, 10, 15, 30 respectively. , 45 and 60 minutes, take an appropriate amount of the solution, filter it, and take the filtrate as the test solution.
  • accurately weigh 5 mg of cefradine reference substance put it in a 50 ml volumetric flask, dissolve and dilute to the mark with acetonitrile-water (70:30), shake well, accurately measure an appropriate amount, and dilute with water to form a solution containing 5 ⁇ g of cefradine per 1 ml.
  • the dissolution amount at different time points was calculated, and the measurement data of the dissolution curve are shown in Table 3.
  • dissolution test method (Second Method of Appendix X C of Chinese Pharmacopoeia 2010 Edition), take 900ml of acetate solution with pH of 4.5 as the solvent, the rotating speed is 100 rpm, operate according to the law, after 5, 10, 15 , 30, 45, 60 minutes, take an appropriate amount of the solution, filter, and take the filtrate as the test solution.
  • accurately weigh 5 mg of cefradine reference substance put it in a 50 ml volumetric flask, dissolve and dilute to the mark with acetonitrile-water (70:30), shake well, accurately measure an appropriate amount, and dilute with water to form a solution containing 5 ⁇ g of cefradine per 1 ml.
  • the dissolution amount at different time points was calculated, and the measurement data of the dissolution curve are shown in Table 4.
  • the most preferred formulation composition is:
  • S1 preparation of raw materials and auxiliary materials: pulverize the raw material cefradine and pass through a screen to obtain cefradine with a particle size of 15-25 microns; then separate microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and stearin. Magnesium acid is passed through a 50-mesh sieve to obtain microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and magnesium stearate that meet the particle size requirements;
  • capsule filling put the above mixed granules into a capsule filling machine for capsule filling to obtain cefradine capsules.
  • the dissolution test conditions refer to Example 1, and the measurement data of the dissolution curve are shown in Table 2;
  • Example 1 900 ml of acetate solution with a pH of 4.5 was used as the dissolution medium, the dissolution test conditions were referred to in Example 1, and the measurement data of the dissolution curve were shown in Table 4.
  • the most preferred formulation composition is:
  • S1 preparation of raw materials and auxiliary materials: pulverize the raw material cefradine and pass through a screen to obtain cefradine with a particle size of 15-25 microns; then separate microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and stearin. Magnesium acid is passed through a 50-mesh sieve to obtain microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and magnesium stearate that meet the particle size requirements;
  • capsule filling put the above mixed granules into a capsule filling machine for capsule filling to obtain cefradine capsules.
  • Example 2 900 ml of phosphate buffer with a pH of 6.8 was used as the dissolution medium, the dissolution test conditions were referred to in Example 1, and the measurement data of the dissolution curve were shown in Table 2.
  • Example 1 900ml of acetate solution with a pH of 4.5 was used as the dissolution medium, the dissolution test conditions were referred to in Example 1, and the measurement data of the dissolution curve were shown in Table 4.
  • Table 1 is the dissolution curve measurement data of Examples 1-3 and reference preparations in aqueous medium.
  • Table 2 is the dissolution curve measurement data of Examples 1-3 and the reference preparation in a phosphate buffer medium with a pH of 6.8.
  • Table 3 is the dissolution curve measurement data of Examples 1-3 and the reference preparation in a hydrochloric acid medium with a pH of 1.2.
  • Table 4 is the dissolution curve measurement data of embodiment 1-3 and reference preparation in the acetate medium of pH 4.5.

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Abstract

本申请公开了一种头孢拉定胶囊的制备方法，包括将头孢拉定与药物辅料混合后进行干法制粒并胶囊填充的步骤。本发明由原来的直接混合改为干法制粒，得到流动性较好的颗粒，使得产品溶出度得到提高,增加药物的生物利用度，外加润滑剂，能够保证产品稳定性和连续生产的可能性。

Description

一种头孢拉定胶囊的制备方法 技术领域
本发明属于医药技术领域，具体涉及一种头孢拉定胶囊的制备方法。
背景技术
头孢拉定(Cephradine,Velosef)别名先锋霉素Ⅵ、头孢菌素Ⅵ等，为第一代半合成头孢菌素，抗菌作用与头孢氨苄相似。本品耐酸可以口服，吸收好，血药浓度较高，特点是耐β内酰胺酶，对耐药性金葡菌及其它多种对广谱抗生素耐药的杆菌等有迅速而可靠的杀菌作用，主要以原形经尿排泄，尿中浓度较高。临床主要用于呼吸道、泌尿道、皮肤和软组织等的感染，如支气管炎、肺炎、肾盂肾炎、膀胱炎、耳鼻咽喉感染、肠炎及痢疾等。
现有的头孢拉定胶囊制备工艺中，通常是将多种药物成分按照一定的顺序直接混合在一起后再进行胶囊填充，胶囊内容物的制备通常有两种工艺：一是粉料混合后直接装填胶囊，该工艺简单、节能省时，由于没有加热工序，适合于原料热敏的品种，要求混粉流动性好；二是通过制粒工艺，制粒又分为湿法制粒和干法制粒，通过制粒工艺，主药可以和辅料紧密结合。
由于头孢拉定为β-内酰胺类抗生素，化学性质不稳定，容易水解，对高温敏感，故不宜采用湿法制粒，而直接混合法中，由于颗粒的流动性较差，产品的稳定性和连续生产的可能性较低，药物的溶出度以及生物利用度均不高。
发明内容
本发明的目的是针对现有技术的不足而提供一种头孢拉定胶囊的制备方法，由原来的直接混合改为干法制粒，得到流动性较好的颗粒，使得产品 溶出度得到提高,增加药物的生物利用度，外加润滑剂，能够保证产品稳定性和连续生产的可能性。
为了完成上述目的，本发明采用以下技术方案：
一种头孢拉定胶囊的制备方法，包括以下步骤：
S1，原料和辅料的准备：将原料头孢拉定粉碎，过筛网，得到符合粒径要求的原料头孢拉定；再分别将填充剂、崩解剂、黏合剂以及润滑剂过第一目数的筛网，得到符合粒径要求的填充剂、崩解剂、黏合剂以及润滑剂；
S2，混合：将头孢拉定、崩解剂、填充剂以及黏合剂加入到频率为10Hz的三维运动混合机中混合10‐15min得到混合药粉；
S3，制粒：再将以上混合药粉加入到干法制粒机中得到破碎的干颗粒；S4，过筛：将破碎的干颗粒过第二目数的筛网整粒，得到干颗粒；
S5，批混：将以上颗粒与润滑剂加入到频率10Hz三维运动混合机中，混合8‐12min；
S6，胶囊充填：将以上混合后的颗粒投入胶囊充填机进行胶囊充填得到头孢拉定胶囊。
作为对本发明的进一步改进，所述崩解剂包括交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠或低取代羟丙基纤维素钠中的一种。
作为对本发明的进一步改进，所述填充剂包括微晶纤维素、微晶纤维素与磷酸氢钙的组合或者微晶纤维素与淀粉的组合中的一种。
作为对本发明的进一步改进，所述润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸或者滑石粉中的一种。
作为对本发明的进一步改进，所述黏合剂包括羧甲纤维素钠、甲基纤维 素或者羟丙基纤维素中的一种。
作为对本发明的进一步改进，所述步骤S1将原料头孢拉定粉碎，过筛网，得到符合粒径要求的原料头孢拉定步骤中，所述符合粒径要求的原料头孢拉定的粒径小于120微米。
作为对本发明的进一步改进，所述步骤S1中，第一目数为30‐70。
作为对本发明的进一步改进，所述步骤S4中，第二目数为15‐25。
与现有技术相比，本发明的有益效果是：
1、本发明主要克服了直接混合工艺物料流动性差不利于连续生产的缺点；本发明采用干法制粒工艺，得到流动性较好的颗粒，外加润滑剂，能够保证产品稳定性和连续生产的可能性。
2、工艺简单、节约了大量人力、物力。
3、按本发明工艺制备的样品，颗粒流动性高，溶出限度均能大于90％，确保头孢拉定胶囊的快速溶出以及生物疗效，提高药物的生物利用度。
具体实施方式
为了使本技术领域的人员更好地理解本申请方案，下面对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
一种头孢拉定胶囊的制备方法，包括将头孢拉定与药物辅料混合后进行干法制粒并胶囊填充的步骤。
进一步的，药物辅料包括崩解剂、填充剂、润滑剂、黏合剂中的一种或 多种。
进一步的，崩解剂包括交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠或低取代羟丙基纤维素钠中的一种，其中，优选为羧甲基淀粉钠、交联羧甲基纤维素钠，最为优选为羧甲基淀粉钠。
进一步的，填充剂包括微晶纤维素、微晶纤维素与磷酸氢钙的组合或者微晶纤维素与淀粉的组合中的一种，其中，最为优选为微晶纤维素。
进一步的，润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸或者滑石粉中的一种，其中，优选为硬脂酸镁、滑石粉，最为优选为硬脂酸镁。
进一步的，黏合剂包括羧甲纤维素钠、甲基纤维素或者羟丙基纤维素中的一种，其中，优选为羧甲纤维素钠、羟丙基纤维素，最为优选为羧甲纤维素钠。
进一步的，以头孢拉定胶囊的总质量为100％计，最优选的处方组成为：
成分 比重
头孢拉定 60％-80％
崩解剂 1％-10％
填充剂 1％-20％
黏合剂 1％-15％
润滑剂 0.5％-1.5％
包括以下步骤：
S1，原料和辅料的准备：将原料头孢拉定粉碎，过筛网，得到符合粒径要求的原料头孢拉定；再分别将填充剂、崩解剂、黏合剂以及润滑剂过第一目数的筛网，得到符合粒径要求的填充剂、崩解剂、黏合剂以及润滑剂；
S2，混合：将头孢拉定、崩解剂、填充剂以及黏合剂加入到频率为10Hz的三维运动混合机中混合10-15min得到混合药粉，优选为混合12min；
S3，制粒：再将以上混合药粉加入到干法制粒机中得到破碎的干颗粒；
S4，过筛：将破碎的干颗粒过第二目数的筛网整粒，得到干颗粒；
S5，批混：将以上颗粒与润滑剂加入到频率10Hz三维运动混合机中，混合8-12min，优选为混合10min；
S6，胶囊充填：将以上混合后的颗粒投入胶囊充填机进行胶囊充填得到头孢拉定胶囊。
在一个实施例中，步骤S1将原料头孢拉定粉碎，过筛网，得到符合粒径要求的原料头孢拉定步骤中，符合粒径要求的原料头孢拉定的粒径小于120微米，优选为小于70微米，最优先为小于40微米。
在一个实施例中，步骤S1中，第一目数为30-70，可根据所需颗粒的粒径进行选择，优选为50。
在一个实施例中，步骤S4中，第二目数为15-25，可根据所需颗粒的粒径进行选择，优选为20。
其中，干法制粒机的参数为搅拌速度25rpm、螺旋转速55-85rpm、压辊转速16rpm、压辊间隙0.9-1.3mm、整粒转速80rpm、压辊压力70bar、整粒筛网孔径1.0mm、真空度0.1bar。
本发明主要克服了直接混合工艺物料流动性差不利于连续生产的缺点；本发明采用干法制粒工艺，得到流动性较好的颗粒，外加润滑剂，能够保证产品稳定性和连续生产的可能性；本发明工艺简单、节约了大量人力、物力；按本发明工艺制备的样品，颗粒流动性高，确保头孢拉定胶囊的快速溶出以及生物疗效，提高药物的生物利用度。
实施例1
以头孢拉定胶囊的总质量为100％计，最优选的处方组成为：
成分 比重
头孢拉定 60％
羧甲基淀粉钠 6％
微晶纤维素 18％
羧甲纤维素钠 15％
硬脂酸镁 1％
包括以下步骤：
S1，原料和辅料的准备：将原料头孢拉定粉碎，过筛网，得到粒径为25-35微米的头孢拉定；再分别将微晶纤维素、羧甲基淀粉钠、羧甲纤维素钠以及硬脂酸镁过50目数的筛网，得到符合粒径要求的微晶纤维素、羧甲基淀粉钠、羧甲纤维素钠以及硬脂酸镁；
S2，混合：将头孢拉定、微晶纤维素、羧甲基淀粉钠以及羧甲纤维素钠加入到频率为10Hz的三维运动混合机中混合12min得到混合药粉；
S3，制粒：再将以上混合药粉加入到干法制粒机中得到破碎的干颗粒；
S4，过筛：将破碎的干颗粒过20目数的筛网整粒，得到干颗粒；
S5，批混：将以上颗粒与硬脂酸镁加入到频率10Hz三维运动混合机中，混合10min；
S6，胶囊充填：将以上混合后的颗粒投入胶囊充填机进行胶囊充填得到头孢拉定胶囊。
以900ml水作为溶出介质，验证头孢拉定胶囊的溶出度，溶出度试验条件如下：
(1)溶出度测定条件
色谱柱：Alltech C 18(150×4.6mm I.D.)
流动相：乙腈-水(60:40)
检测波长：UV 220nm
流速：2.0ml/min
进样量：20μl
(2)溶出度实验方法
照溶出度测定法(中国药典2010版二部附录X C第二法)，以水900ml为溶剂，转速为每分钟100转，依法操作，分别经5、10、15、30、45、60分钟时取溶液适量，滤过，取续滤液作为供试品溶液。另精密称取头孢拉定对照品5mg，置50ml容量瓶中，用乙腈-水(70:30)溶解并稀释至刻度，摇匀，精密量取适量，用水稀释成每1ml中含头孢拉定5μg的溶液，作为对照品溶液，计算出不同时间点的溶出量，溶出曲线测定数据如表一所示。
以900mlpH为6.8的磷酸盐缓冲液作为溶出介质，验证头孢拉定胶囊的溶出度，溶出度试验条件如下：
(1)溶出度测定条件
色谱柱：Alltech C 18(150×4.6mm I.D.)
流动相：乙腈-水(60:40)
检测波长：UV 220nm
流速：2.0ml/min
进样量：20μl
(2)溶出度实验方法
照溶出度测定法(中国药典2010版二部附录X C第二法)，以900mlpH为6.8的磷酸盐缓冲液为溶剂，转速为每分钟100转，依法操作，分别经5、10、15、30、45、60分钟时取溶液适量，滤过，取续滤液作为供试品溶液。另精密称取头孢拉定对照品5mg，置50ml容量瓶中，用乙腈-水(70:30)溶 解并稀释至刻度，摇匀，精密量取适量，用水稀释成每1ml中含头孢拉定5μg的溶液，作为对照品溶液，计算出不同时间点的溶出量，溶出曲线测定数据如表二所示。
以900mlpH为1.2的盐酸溶液作为溶出介质，验证头孢拉定胶囊的溶出度，溶出度试验条件如下：
(1)溶出度测定条件
色谱柱：Alltech C 18(150×4.6mm I.D.)
流动相：乙腈-水(60:40)
检测波长：UV 220nm
流速：2.0ml/min
进样量：20μl
(2)溶出度实验方法
照溶出度测定法(中国药典2010版二部附录X C第二法)，以900ml pH为1.2的盐酸溶液为溶剂，转速为每分钟100转，依法操作，分别经5、10、15、30、45、60分钟时取溶液适量，滤过，取续滤液作为供试品溶液。另精密称取头孢拉定对照品5mg，置50ml容量瓶中，用乙腈-水(70:30)溶解并稀释至刻度，摇匀，精密量取适量，用水稀释成每1ml中含头孢拉定5μg的溶液，作为对照品溶液，计算出不同时间点的溶出量，溶出曲线测定数据如表三所示。
以900mlpH为4.5的醋酸盐溶液作为溶出介质，验证头孢拉定胶囊的溶出度，溶出度试验条件如下：
(1)溶出度测定条件
色谱柱：Alltech C 18(150×4.6mm I.D.)
流动相：乙腈-水(60:40)
检测波长：UV 220nm
流速：2.0ml/min
进样量：20μl
(2)溶出度实验方法
照溶出度测定法(中国药典2010版二部附录X C第二法)，以900ml pH为4.5的醋酸盐溶液为溶剂，转速为每分钟100转，依法操作，分别经5、10、15、30、45、60分钟时取溶液适量，滤过，取续滤液作为供试品溶液。另精密称取头孢拉定对照品5mg，置50ml容量瓶中，用乙腈-水(70:30)溶解并稀释至刻度，摇匀，精密量取适量，用水稀释成每1ml中含头孢拉定5μg的溶液，作为对照品溶液，计算出不同时间点的溶出量，溶出曲线测定数据如表四所示。
实施例2
以头孢拉定胶囊的总质量为100％计，最优选的处方组成为：
成分 比重
头孢拉定 60％
羧甲基淀粉钠 6％
微晶纤维素 18％
羧甲纤维素钠 15％
硬脂酸镁 1％
包括以下步骤：
S1，原料和辅料的准备：将原料头孢拉定粉碎，过筛网，得到粒径为15-25微米的头孢拉定；再分别将微晶纤维素、羧甲基淀粉钠、羧甲纤维素钠以及硬脂酸镁过50目数的筛网，得到符合粒径要求的微晶纤维素、羧甲基淀粉 钠、羧甲纤维素钠以及硬脂酸镁；
S2，混合：将头孢拉定、微晶纤维素、羧甲基淀粉钠以及羧甲纤维素钠加入到频率为10Hz的三维运动混合机中混合12min得到混合药粉；
S3，制粒：再将以上混合药粉加入到干法制粒机中得到破碎的干颗粒；
S4，过筛：将破碎的干颗粒过20目数的筛网整粒，得到干颗粒；
S5，批混：将以上颗粒与硬脂酸镁加入到频率10Hz三维运动混合机中，混合10min；
S6，胶囊充填：将以上混合后的颗粒投入胶囊充填机进行胶囊充填得到头孢拉定胶囊。
以900ml水作为溶出介质，验证头孢拉定胶囊的溶出度，溶出度试验条件参照实施例1，溶出曲线测定数据如表一所示；
以900mlpH为6.8的磷酸盐缓冲液作为溶出介质，溶出度试验条件参照实施例1，溶出曲线测定数据如表二所示；
以900mlpH为1.2的盐酸溶液作为溶出介质，溶出度试验条件参照实施例1，溶出曲线测定数据如表三所示；
以900mlpH为4.5的醋酸盐溶液作为溶出介质，溶出度试验条件参照实施例1，溶出曲线测定数据如表四所示。
实施例3
以头孢拉定胶囊的总质量为100％计，最优选的处方组成为：
成分 比重
头孢拉定 60％
羧甲基淀粉钠 6％
微晶纤维素 18％
羧甲纤维素钠 15％
硬脂酸镁 1％
包括以下步骤：
S1，原料和辅料的准备：将原料头孢拉定粉碎，过筛网，得到粒径为15-25微米的头孢拉定；再分别将微晶纤维素、羧甲基淀粉钠、羧甲纤维素钠以及硬脂酸镁过50目数的筛网，得到符合粒径要求的微晶纤维素、羧甲基淀粉钠、羧甲纤维素钠以及硬脂酸镁；
S2，混合：将头孢拉定、微晶纤维素、羧甲基淀粉钠以及羧甲纤维素钠加入到频率为10Hz的三维运动混合机中混合12min得到混合药粉；
S3，制粒：再将以上混合药粉加入到干法制粒机中得到破碎的干颗粒；
S4，过筛：将破碎的干颗粒过20目数的筛网整粒，得到干颗粒；
S5，批混：将以上颗粒与硬脂酸镁加入到频率10Hz三维运动混合机中，混合10min；
S6，胶囊充填：将以上混合后的颗粒投入胶囊充填机进行胶囊充填得到头孢拉定胶囊。
以900ml水作为溶出介质，验证头孢拉定胶囊的溶出度，溶出度试验条件参照实施例1，溶出曲线测定数据如表一所示。
以900mlpH为6.8的磷酸盐缓冲液作为溶出介质，溶出度试验条件参照实施例1，溶出曲线测定数据如表二所示。
以900mlpH为1.2的盐酸溶液作为溶出介质，溶出度试验条件参照实施例1，溶出曲线测定数据如表三所示。
以900mlpH为4.5的醋酸盐溶液作为溶出介质，溶出度试验条件参照实施例1，溶出曲线测定数据如表四所示。
表一为实施例1-3与参比制剂在水介质中的溶出曲线测定数据。
表二为实施例1-3与参比制剂在PH为6.8的磷酸盐缓冲液介质中的溶出曲线测定数据。
表三为实施例1-3与参比制剂在PH为1.2的盐酸介质中的溶出曲线测定数据。
表四为实施例1-3与参比制剂在PH为4.5的醋酸盐介质中的溶出曲线测定数据。
参比制剂：头孢拉定胶囊；生产厂家：上海施贵宝制药有限公司，溶出度试验条件如下：取900ml溶出介质，桨法100转，照溶出度与释放度测定法(通则0901第一法)测定。
表一
Figure PCTCN2021093546-appb-000001
表二
Figure PCTCN2021093546-appb-000002
表三
Figure PCTCN2021093546-appb-000003
表四
Figure PCTCN2021093546-appb-000004
Figure PCTCN2021093546-appb-000005
虽然本发明已利用上述较佳实施例进行说明，但其并非用以限定本发明的保护范围，任何本领域技术人员在不脱离本发明的精神和范围之内，相对上述实施例进行各种变动与修改仍属于本发明所保护的范围。

Claims (8)

  1. 一种头孢拉定胶囊的制备方法，其特征在于，包括以下步骤：
    S1，原料和辅料的准备：将原料头孢拉定粉碎，过筛网，得到符合粒径要求的原料头孢拉定；再分别将填充剂、崩解剂、黏合剂以及润滑剂过第一目数的筛网，得到符合粒径要求的填充剂、崩解剂、黏合剂以及润滑剂；
    S2，混合：将头孢拉定、崩解剂、填充剂以及黏合剂加入到频率为10Hz的三维运动混合机中混合10-15min得到混合药粉；
    S3，制粒：再将以上混合药粉加入到干法制粒机中得到破碎的干颗粒；
    S4，过筛：将破碎的干颗粒过第二目数的筛网整粒，得到干颗粒；
    S5，批混：将以上颗粒与润滑剂加入到频率10Hz三维运动混合机中，混合8-12min；
    S6，胶囊充填：将以上混合后的颗粒投入胶囊充填机进行胶囊充填得到头孢拉定胶囊。
  2. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述崩解剂包括交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠或低取代羟丙基纤维素钠中的一种。
  3. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述填充剂包括微晶纤维素、微晶纤维素与磷酸氢钙的组合或者微晶纤维素与淀粉的组合中的一种。
  4. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述润滑剂包括硬脂酸镁、硬脂酸钙、硬脂酸或者滑石粉中的一种。
  5. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述黏合剂包括羧甲纤维素钠、甲基纤维素或者羟丙基纤维素中的一种。
  6. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述步骤S1将原料头孢拉定粉碎，过筛网，得到符合粒径要求的原料头孢拉定步骤中，所述符合粒径要求的原料头孢拉定的粒径小于120微米。
  7. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述步骤S1中，第一目数为30-70。
  8. 根据权利要求1所述的一种头孢拉定胶囊的制备方法，其特征在于，所述步骤S4中，第二目数为15-25。
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