CN112569196B - 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 PDFInfo
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- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 title claims abstract description 47
- 229960002291 clindamycin phosphate Drugs 0.000 title claims abstract description 47
- 239000000003 vaginal tablet Substances 0.000 title claims abstract description 35
- 229940044977 vaginal tablet Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 20
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 18
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 18
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 13
- 239000008101 lactose Substances 0.000 claims abstract description 13
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 12
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 6
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- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 abstract description 5
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000001133 acceleration Effects 0.000 description 3
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- 239000003242 anti bacterial agent Substances 0.000 description 2
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- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
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- 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
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
本发明提供一种克林霉素磷酸酯阴道片及其制备工艺,所述克林霉素磷酸酯阴道片,由包括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。本发明制得克林霉素磷酸酯阴道片溶胀速率良好,而且具有较大黏附力,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。
Description
技术领域
本发明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,已列入治疗威胁人类健康和生命的多种感染的高效抗菌药品之一。克林霉素已被中国、美国、英国、日本等多国收入药典。
克林霉素磷酸酯(clindamycin phosphate)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的半合成抗菌药物,为半合成抗生素,相比克林霉素,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,为阴道给药,于晚上临睡前清洗外阴后,将本品放入阴道后穹隆处,用于治疗细菌性阴道炎。部分患者使用时药片出现脱落情况,尤其在天气干燥时,影响阴道片使用效果。
发明内容
鉴于此,本发明提出一种克林霉素磷酸酯阴道片及其制备工艺,以解决上述技术问题。
本发明的技术方案是这样实现的:
一种克林霉素磷酸酯阴道片,由包括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。
进一步的,所述羟丙甲纤维素为低取代羟丙甲纤维素。
本发明提供一种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、乳糖分多次混合搅拌,得初混物;
S2、取初混物,加入羟丙甲纤维素水溶液,制软材,过筛制粒,得软粒;
S3、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。
进一步的,S1步骤中,分多次混合搅拌具体为: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。
进一步的,S2步骤中,采用流化床底喷包衣技术,将羟丙甲纤维素水溶液喷至初混物。
进一步的,所述流化床底喷包衣技术的工艺条件:进风温度38-42℃,风量23-28HZ,雾化压力0.4~0.5MPa,喷液速率35-45ml/min。
进一步的,S3步骤中,所述干燥的时间为2-4小时。
进一步的,S2步骤中,所述过筛的目数为16-18目。
进一步的,S3步骤中,所述过筛的目数为14-16目。
与现有技术相比,本发明的有益效果是:
(1)本发明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,优选配比,制得克林霉素磷酸酯阴道片溶胀速率良好,具有较大黏附力,有效避免使用时药片脱落,有效提高使用舒适性,而且样品稳定性良好,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,本发明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,优化工艺后,不仅减少了羟丙甲纤维素水溶液使用量及干燥时间,而且制得克林霉素磷酸酯阴道片的溶胀速率与黏附力性能更优。优化后工艺在保障片剂质量的前提下,缩短生产时间,提高生产效率。
具体实施方式
为了更好理解本发明技术内容,下面提供具体实施例,对本发明做进一步的说明。
本发明实施例所用的实验方法如无特殊说明,均为常规方法。
本发明实施例所用的材料、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)
(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、取初混物,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、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)
(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)
(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)
(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、取初混物,采用流化床底喷包衣技术,将2.0wt%羟丙甲纤维素水溶液喷至初混物,进风温度40℃,风量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、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)
(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)
(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W0。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-W0)/W0]×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:
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,本发明实施例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)=mg,g为重量系数,9.8计。结果见表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,本发明实施例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区别在于工艺,在优化工艺后,不仅减少羟丙甲纤维素水溶液使用量、减少干燥时间,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:
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:
参见上述加速试验以及长期试验结果,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。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种克林霉素磷酸酯阴道片,其特征在于,由包括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;
所述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、乳糖分多次混合搅拌,得初混物;
S2、取初混物,加入羟丙甲纤维素水溶液,制软材,过筛制粒,得软粒;
S3、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;
S1步骤中,分多次混合搅拌具体为: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;
S2步骤中,采用流化床底喷包衣技术,将羟丙甲纤维素水溶液喷至初混物;
所述流化床底喷包衣技术的工艺条件:进风温度38-42℃,风量23-28HZ,雾化压力0.4~0.5MPa,喷液速率35-45ml/min。
2.根据权利要求1所述的一种克林霉素磷酸酯阴道片,其特征在于,由包括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。
3.根据权利要求1所述的一种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所述的一种克林霉素磷酸酯阴道片,其特征在于,S3步骤中,所述干燥的时间为2-4小时。
5.根据权利要求1所述的一种克林霉素磷酸酯阴道片,其特征在于,S2步骤中,所述过筛的目数为16-18目。
6.根据权利要求1所述的一种克林霉素磷酸酯阴道片,其特征在于,S3步骤中,所述过筛的目数为14-16目。
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