WO2022142150A1 - 一种克林霉素磷酸酯阴道片及其制备工艺 - Google Patents

一种克林霉素磷酸酯阴道片及其制备工艺 Download PDF

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WO2022142150A1
WO2022142150A1 PCT/CN2021/099450 CN2021099450W WO2022142150A1 WO 2022142150 A1 WO2022142150 A1 WO 2022142150A1 CN 2021099450 W CN2021099450 W CN 2021099450W WO 2022142150 A1 WO2022142150 A1 WO 2022142150A1
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clindamycin phosphate
parts
vaginal tablet
tablet according
preparation technology
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PCT/CN2021/099450
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English (en)
French (fr)
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韦家华
刘玉
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海南海神同洲制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/2022—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the application relates to the technical field of pharmaceutical preparations, in particular to a vaginal tablet of clindamycin phosphate and a preparation process thereof.
  • Clindamycin is a lincosamide antibiotic with strong antibacterial activity and broad antibacterial spectrum, which is suitable for the treatment of many infectious diseases in various clinical departments.
  • Clindamycin phosphate (clindamycin phosphate) is a semi-synthetic derivative of clindamycin, which can be hydrolyzed into clindamycin to exert antibacterial effect after being absorbed. It is widely used in Gram-positive cocci and anaerobic bacteria. Infection, clindamycin phosphate can effectively reduce adverse reactions compared with clindamycin.
  • the main preparations of clindamycin phosphate are injection, gel, oral tablet, etc.
  • Clindamycin Phosphate Vaginal Tablets are administered vaginally for the treatment of bacterial vaginosis. This product is usually placed in the posterior fornix of the vagina after cleansing the vulva at night before going to bed. Some patients, especially when using vaginal tablets in dry weather, may experience the situation that the tablets fall off, which affects the effect of vaginal tablets.
  • the present application proposes a clindamycin phosphate vaginal tablet and a preparation process thereof to solve the above problems.
  • a first aspect of the present application provides a clindamycin phosphate vaginal tablet, which is prepared from the following raw materials by weight: 125 parts of clindamycin phosphate, 140-160 parts of lactose, and 90-95 parts of microcrystalline cellulose , 7-8 parts of sodium starch glycolate, 1.5-2.0 parts of magnesium stearate, 10-20 parts of 1.8-2.2wt% hypromellose aqueous solution.
  • the clindamycin phosphate vaginal tablet can be made from the following raw materials by weight: 125 parts of clindamycin phosphate, 150 parts of lactose, 93 parts of microcrystalline cellulose, 7.5 parts of sodium starch glycolate, stearic acid 1.85 parts of magnesium, 10 parts of 2.0 wt% hypromellose aqueous solution.
  • the hypromellose may be low-substituted hypromellose.
  • the second aspect of the present application provides the preparation process of clindamycin phosphate vaginal tablet, comprising the following steps:
  • Clindamycin phosphate, microcrystalline cellulose and lactose are mixed and stirred for several times to obtain an initial mixture
  • the mixing and stirring may include: firstly heating and melting microcrystalline cellulose, adding clindamycin phosphate, mixing and stirring for the first time, cooling and then adding to the melted lactose, Carry out the second mixing and stirring to obtain the initial mixture.
  • step S2 the hypromellose aqueous solution is sprayed onto the initial mixture by a fluidized bed bottom spray coating method.
  • the fluidized bed bottom spray coating method used in this application is a conventional method used in the coating process in the pharmaceutical process, and it can be realized by a Wurster type bottom spray fluidized bed. During the coating process using this method, the coated drug particles are suspended in the fluidized air flow, and the coating liquid sprayed from the bottom of the fluidized bed contacts the drug particles to complete the coating process.
  • the process conditions of the fluidized bed bottom spray coating method may include: inlet air temperature 38-42°C, outlet air frequency 23-28Hz, atomization pressure 0.4-0.5MPa, and liquid spray rate 35-45ml/min.
  • the drying time may be 2-4 hours.
  • the mesh number of the sieve can be 16-18 mesh.
  • the mesh number of the sieve can be 14-16 mesh.
  • the application takes clindamycin phosphate as the main drug, and taking lactose as a diluent and a hygroscopic agent, microcrystalline cellulose as a diluent, sodium starch glycolate as a disintegrant, and magnesium stearate as a lubricant, Using hypromellose aqueous solution as binder.
  • the obtained clindamycin phosphate vaginal tablet has a good swelling rate and a large adhesive force, effectively avoids the problem of the tablet falling off during use, and improves the use comfort, and the clindamycin phosphate of the present application Clindamycin phosphate vaginal tablets have good stability, can better exert the efficacy of clindamycin, shorten the medication time, and improve the patient's compliance.
  • the present application not only reduces hypromellose by mixing clindamycin phosphate with microcrystalline cellulose and lactose after melting successively, and adopting the optimization process of fluidized bed bottom spray coating technology
  • the usage amount and drying time of the aqueous solution are better, and the swelling rate and adhesion performance of the prepared clindamycin phosphate vaginal tablet are better.
  • the process of the present application shortens the production time and improves the production efficiency under the premise of ensuring the quality of the tablet.
  • the soft granules are dried at 50-55 °C for 4 hours, and then passed through a 14-mesh sieve to granulate;
  • the soft granules are dried at 50-55 °C for 2 hours, and then passed through a 14-mesh sieve to granulate;
  • the clindamycin phosphate vaginal tablets prepared in Examples 1-4 and Comparative 1-2 meet the requirements of the 2015 edition of the Chinese Pharmacopoeia in terms of properties, melting time limit, content determination, and related substances.
  • the vaginal tablet is placed in a stainless steel mesh basket and the initial weight W 0 is weighed. Soak the mesh basket in a beaker containing 100mL of distilled water (room temperature is 25°C), take it out at 10, 20, 30, 40, 50, 60, and 90 minutes, absorb the moisture on the surface of the mesh basket with filter paper, and weigh W , calculate the weight gain percentage of each vaginal tablet at different time.
  • the percentage of weight gain versus time was regressed to a straight line, and the slope was the swelling rate of the vaginal tablet. The results are shown in Table 1:
  • mice were sacrificed by cervical dislocation, and the abdominal mucosa was taken and firmly adhered to the platform.
  • a hard ring slightly larger than the tablet is set on the tablet, and the hard ring is connected with a plastic cup through a fixed pulley.
  • Use an infusion dropper to drip water into the cup until the vaginal patch separates from the mucosa.
  • the results are shown in Table 2:
  • Example 4 adopts the fluidized bed bottom spray coating technology, which not only reduces the amount of hypromellose aqueous solution used, reduces the drying time, but also makes the preparation of Clindamycin The swelling rate and adhesion performance of the plain phosphate vaginal tablets were better.
  • Example 4 The sample of clindamycin phosphate vaginal tablet prepared in Example 4 was packaged in a composite film bag and placed in an accelerated stability test box for testing. Temperature: 40 ⁇ 2°C, relative humidity: 75 ⁇ 5%, accelerated test for 6 months, the results are shown in Table 3.
  • Example 4 The sample of clindamycin phosphate vaginal tablet prepared in Example 4 was packaged in a composite film bag and placed in an accelerated stability test box for testing. Temperature: 25 ⁇ 2°C, relative humidity: 60 ⁇ 5%, long-term test for 24 months, the results are shown in Table 4.
  • the inspection indexes such as the appearance properties, melting time limit, related substances, and content of the clindamycin phosphate vaginal tablet obtained in Example 4 all meet the requirements of the pharmacopoeia, and show that the sample has good stability.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

一种克林霉素磷酸酯阴道片，由以下重量份的原料制成：克林霉素磷酸酯125份、乳糖140-160份、微晶纤维素90-95份、羧甲淀粉钠7-8份、硬脂酸镁1.5-2.0份、1.8-2.2wt％的羟丙甲纤维素水溶液10-20份。一种克林霉素磷酸酯阴道片的制备方法。

Description

一种克林霉素磷酸酯阴道片及其制备工艺 技术领域
本申请涉及药物制剂技术领域，特别涉及一种克林霉素磷酸酯阴道片及其制备工艺。
背景技术
克林霉素是一种林可胺类抗生素，抗菌活性强，抗菌谱广，适用于治疗临床各科许多感染性疾病。
克林霉素磷酸酯(clindamycin phosphate)为半合成的克林霉素衍生物，其被吸收后可水解成克林霉素发挥抗菌作用，广泛应用于革兰阳性球菌及厌氧菌所致严重感染，相比克林霉素，克林霉素磷酸酯能够有效减少不良反应。克林霉素磷酸酯主要制剂有注射液、凝胶、口服片剂等。克林霉素磷酸酯阴道片，通过阴道给药的方式，用于治疗细菌性阴道炎。通常于晚上临睡前清洗外阴后，将本品放入阴道后穹隆处。部分患者，尤其在天气干燥时使用阴道片会出现药片脱落的情况，影响阴道片使用效果。
发明内容
鉴于此，本申请提出一种克林霉素磷酸酯阴道片及其制备工艺，以解决上述问题。
本申请第一方面提供了一种克林霉素磷酸酯阴道片，由以下重量份的原料制成：克林霉素磷酸酯125份、乳糖140-160份、微晶纤维素90-95份、羧甲淀粉钠7-8份、硬脂酸镁1.5-2.0份、1.8-2.2wt％羟丙甲纤维素水溶液10-20份。
优选地，克林霉素磷酸酯阴道片可由以下重量份的原料制成：克林霉素磷酸酯125份、乳糖150份、微晶纤维素93份、羧甲淀粉钠7.5份、硬脂酸镁1.85份、2.0wt％羟丙甲纤维素水溶液10份。
优选地，所述羟丙甲纤维素可为低取代羟丙甲纤维素。
本申请第二方面提供了克林霉素磷酸酯阴道片的制备工艺，包括以下步骤：
S1、将克林霉素磷酸酯、微晶纤维素和乳糖分多次混合搅拌，得初混物；
S2、向初混物中加入羟丙甲纤维素水溶液，制软材，过筛制粒，得软粒；
S3、将软粒置于50-55℃干燥，过筛整粒；
S4、加入硬脂酸镁和羧甲基淀粉钠，混合，压片。
优选地，S1步骤中，分多次混合搅拌可包括：先将微晶纤维素加热熔融，加入克林霉素磷酸酯，进行第一次混合搅拌，冷却后再加入到熔融后的乳糖中，进行第二次混合搅拌，得初混物。
优选地，S2步骤中，采用流化床底喷包衣方法将羟丙甲纤维素水溶液喷至初混物。
本申请中所使用的流化床底喷包衣方法是制药过程中包衣工序所使用的常规方法，其可以通过Wurster型底喷式流化床来实现。在使用该方法进行包衣的过程中，被包覆的药物颗粒悬浮于流化气流中，从流化床底部喷射的包衣液与药物颗粒接触并完成包衣过程。
优选地，流化床底喷包衣方法的工艺条件可包括：进风温度38-42℃，出风频率23-28Hz，雾化压力0.4～0.5MPa，喷液速率35-45ml/min。
优选地，S3步骤中，干燥的时间可为2-4小时。
优选地，S2步骤中，过筛的目数可为16-18目。
优选地，S3步骤中，过筛的目数可为14-16目。
与现有技术相比，本申请具有以下的有益效果。
(1)本申请以克林霉素磷酸酯为主药，以乳糖为稀释剂兼吸湿剂、微晶纤维素为稀释剂、羧甲淀粉钠为崩解剂、硬脂酸镁为润滑剂，以羟丙甲纤维素水溶液为粘合剂。通过优选配比，制得的克林霉素磷酸酯阴道片溶胀速率良好，具有较大黏附力，有效避免了使用时药片脱落的问题，并提高了使用舒适性，而且本申请的克林霉素磷酸酯阴道片稳定性良好，可以更好发挥克林霉素药效，缩短用药时间，提高患者使用依从性。
(2)进一步地，本申请通过将克林霉素磷酸酯依次与熔融后微晶纤维素、乳糖混合，并采用流化床底喷包衣技术的优化工艺，不仅减少了羟丙甲纤维素水溶液使用量及干燥时间，而且制得的克林霉素磷酸酯阴道片的溶胀速率与黏 附力性能更优。本申请的工艺在保障片剂质量的前提下，缩短了生产时间，提高了生产效率。
具体实施方式
为了更好理解本申请技术内容，下面提供具体实施例，对本申请做进一步的说明。
本申请实施例所用的实验方法如无特殊说明，均为常规方法。
本申请实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1-克林霉素磷酸酯阴道片制备
(1)处方(按每1000片计算)
Figure PCTCN2021099450-appb-000001
(2)工艺
S1、先将微晶纤维素加热熔融，加入克林霉素磷酸酯，进行第一次混合搅拌5min，冷却后再加入到熔融后的乳糖中，进行第二次混合搅拌10min，得初混物；
S2、向初混物中加入2wt％低取代羟丙甲纤维素水溶液；制软材，过16目筛制粒，得软粒；
S3、将软粒置于50-55℃干燥4h，过14目筛整粒；
S4、加入硬脂酸镁和羧甲基淀粉钠，混合10min，压片。
实施例2-克林霉素磷酸酯阴道片制备
(1)处方(按每1000片计算)
Figure PCTCN2021099450-appb-000002
(2)工艺与实施例1一致。
实施例3-克林霉素磷酸酯阴道片制备
(1)处方(按每1000片计算)
Figure PCTCN2021099450-appb-000003
(2)工艺与实施例1一致。
实施例4-克林霉素磷酸酯阴道片制备
(1)处方(按每1000片计算)
Figure PCTCN2021099450-appb-000004
Figure PCTCN2021099450-appb-000005
(2)工艺
S1、先将微晶纤维素加热熔融，加入克林霉素磷酸酯，进行第一次混合搅拌5min，冷却后再加入到熔融后的乳糖中，进行第二次混合搅拌10min，得初混物；
S2、采用流化床底喷包衣方法，将2.0wt％羟丙甲纤维素水溶液喷至初混物，其中流化床底喷包衣方法的工艺条件包括：进风温度40℃，出风频率25Hz，雾化压力0.43MPa，喷液速率40ml/min，制软材，过16目筛制粒，得软粒；
S3、将软粒置于50-55℃干燥2h，过14目筛整粒；
S4、加入硬脂酸镁和羧甲基淀粉钠，混合10min，压片。
对比例1克林霉素磷酸酯阴道片
本对比例与实施例1区别在于组分用量不同：
(1)处方(按每1000片计算)
Figure PCTCN2021099450-appb-000006
(2)工艺与实施例1一致。
对比例2克林霉素磷酸酯阴道片
本对比例与实施例1区别在于组分用量不同：
(1)处方(按每1000片计算)
Figure PCTCN2021099450-appb-000007
Figure PCTCN2021099450-appb-000008
(2)工艺与实施例1一致。
试验例
(1)基本检查
实施例1-4以及对比1-2制得的克林霉素磷酸酯阴道片，性状、融变时限、含量测定、有关物质均符合中国药典2015年版要求。
(2)溶胀速率的测定
将阴道片放入不锈钢网篮中，称量初始重量W 0。把网篮置于盛有100mL蒸馏水的烧杯中浸泡(室温25℃)，于10、20、30、40、50、60、90min时取出，用滤纸吸干网篮表面的水分，称量重量W，计算不同时间各阴道片的增重百分率。增重百分率的计算公式为：增重％＝[(W-W 0)/W 0]×100％。将增重百分率对时间回归得一直线，斜率即为阴道片的溶胀速率。结果见表1：
表1
  溶胀速率
实施例1 0.0985
实施例2 0.0974
实施例3 0.0969
实施例4 0.1028
对比例1 0.0879
对比例2 0.0893
根据上表结果可知，与对比例1-2相比，本申请实施例1-4制得克林霉素磷酸酯阴道片溶胀速率良好。
(3)黏附力的测定
将小鼠断颈处死，取腹黏膜牢固黏贴在平台上。测定时先用20μL蒸馏水将黏膜湿润，然后将阴道片与黏膜层贴紧，加砝码200g压迫2min。在药片上套一个比药片稍大的硬环，硬环通过定滑轮与一塑料杯连结。用输液滴管向杯中滴水，直到阴道片与黏膜分离为止。称量塑料杯及水的质量m，计算黏附力。黏附力的计算公式为：黏附力(N)＝m*g，g为重量系数，按照9.8计。结果见表2：
表2
  黏附力(N)
实施例1 0.69
实施例2 0.67
实施例3 0.65
实施例4 0.74
对比例1 0.45
对比例2 0.53
根据上表结果可知，与对比例1-2相比，本申请实施例1-4制得克林霉素磷酸酯阴道片的黏附力性能更优。
其中实施例4与实施例1区别在于实施例4采用了流化床底喷包衣技术，由此不仅减少了羟丙甲纤维素水溶液使用量、减少了干燥时间，还使得制得克林霉素磷酸酯阴道片的溶胀速率与黏附力性能更优。
(4)稳定性考察
1)加速试验
将实施例4制得克林霉素磷酸酯阴道片样品用复合膜袋包装好，置于稳定性加速试验箱内试验。温度：40±2℃，相对湿度：75±5％，加速试验6个月，结果见表3。
表3
Figure PCTCN2021099450-appb-000009
2)长期试验
将实施例4制得克林霉素磷酸酯阴道片样品用复合膜袋包装好，置于稳定性加速试验箱内试验。温度：25±2℃，相对湿度：60±5％，长期试验24个月，结果见表4。
表4
Figure PCTCN2021099450-appb-000010
参见上述加速试验以及长期试验结果，实施例4制得克林霉素磷酸酯阴道片的外观性状、融变时限、有关物质、含量等考察指标均符合药典要求，显示样品稳定性良好。
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (10)

  1. 一种克林霉素磷酸酯阴道片，其特征在于，由以下重量份的原料制成：克林霉素磷酸酯125份、乳糖140-160份、微晶纤维素90-95份、羧甲淀粉钠7-8份、硬脂酸镁1.5-2.0份、1.8-2.2wt％的羟丙甲纤维素水溶液10-20份。
  2. 根据权利要求1所述的克林霉素磷酸酯阴道片，其特征在于，由以下重量份的原料制成：克林霉素磷酸酯125份、乳糖150份、微晶纤维素93份、羧甲淀粉钠7.5份、硬脂酸镁1.85份、2.0wt％的羟丙甲纤维素水溶液10份。
  3. 根据权利要求1所述的克林霉素磷酸酯阴道片，其特征在于，所述羟丙甲纤维素为低取代羟丙甲纤维素。
  4. 根据权利要求1-3任一项所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，包括以下步骤：
    S1、将克林霉素磷酸酯、微晶纤维素和乳糖分多次混合搅拌，得初混物；
    S2、向初混物中加入羟丙甲纤维素水溶液，制软材，过筛制粒，得软粒；
    S3、将软粒置于50-55℃干燥，过筛整粒；
    S4、加入硬脂酸镁和羧甲基淀粉钠，混合，压片。
  5. 根据权利要求4所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，S1步骤中，分多次混合搅拌包括：将微晶纤维素加热熔融，加入克林霉素磷酸酯，进行第一次混合搅拌，冷却后再加入到熔融后的乳糖中，进行第二次混合搅拌，得到所述初混物。
  6. 根据权利要5所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，S2步骤中，采用流化床底喷包衣方法将羟丙甲纤维素水溶液喷至所述初混物。
  7. 根据权利要求6所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，所述流化床底喷包衣方法的工艺条件包括：进风温度38-42℃，出风频率23-28Hz，雾化压力0.4～0.5MPa，喷液速率35-45ml/min。
  8. 根据权利要求5所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，S3步骤中，所述干燥的时间为2-4小时。
  9. 根据权利要求5所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，S2步骤中，过筛所用筛网的目数为16-18目。
  10. 根据权利要求5所述的克林霉素磷酸酯阴道片的制备工艺，其特征在于，S3步骤中，过筛所用筛网的目数为14-16目。
PCT/CN2021/099450 2020-12-30 2021-06-10 一种克林霉素磷酸酯阴道片及其制备工艺 WO2022142150A1 (zh)

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