CN111110641A - 一种左氧氟沙星片剂组合物及其制备方法 - Google Patents
一种左氧氟沙星片剂组合物及其制备方法 Download PDFInfo
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- CN111110641A CN111110641A CN201811282056.5A CN201811282056A CN111110641A CN 111110641 A CN111110641 A CN 111110641A CN 201811282056 A CN201811282056 A CN 201811282056A CN 111110641 A CN111110641 A CN 111110641A
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- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 99
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
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- 229960001681 croscarmellose sodium Drugs 0.000 claims description 27
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
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- 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
- A61K9/2009—Inorganic compounds
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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
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- 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
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明属于医药技术领域,具体涉及一种左氧氟沙星片剂组合物及其制备方法,所述的药物组合物含有左氧氟沙星、填充剂、润滑剂、崩解剂、粘合剂、油酸。本发明的本发明的产品稳定性好,溶出完全,具有更加优秀的产品质量;本发明的产品生产操作简单易行,适合于工业生产。
Description
技术领域
本发明属于医药技术领域,具体涉及一种左氧氟沙星片剂组合物及其制备方法。
背景技术
左氧氟沙星(Levofloxac)是氧氟沙星的左旋光学活性L-型异构体,其抗菌活性约为氧氟沙星的2倍,具有抗菌谱广、抗菌作用强的特点。对大多数肠杆菌科细菌,如大肠埃希菌、克雷白菌属、沙雷菌属、变形杆菌属、志贺菌属、沙门菌属、枸橼酸杆菌、不动杆菌属以及铜绿假单胞菌、流感嗜血杆菌、淋球菌等革兰阴性细菌有较强的抗菌活性。对部分甲氧西林敏感葡萄球菌、肺炎链球菌、化脓性链球菌、溶血性链球菌等革兰阳性菌和军团菌、支原体、衣原体也有良好的抗菌作用,但对厌氧菌和肠球菌的作用较差。
左氧氟沙星化学名为(S)-(-)-9-氟-2,3-二氢-3-甲基-10-(4-甲基-1-哌嗪)-7-氧-7H-吡啶骈[1,2,3-de]-[1,4]苯并噁嗪-6-羧酸,在小肠的pH下以两性离子形式存在,商业化使用其半水合物,分子式C18H20FN3O4·1/2H2O,结构式如下:
左氧氟沙星为白色至类白色粉末,其溶解性呈pH依赖性。20℃测定时,左氧氟沙星在水中的溶解度约25mg/ml,在pH2-5范围内,溶解度基本上恒定,约为200mg/ml;在约pH6.5时增加到最大值,约300mg/ml;在pH6.5以上时,溶解度降低,并在约pH7.5达到其最小值,约30mg/ml。左氧氟沙星在甲醇中略溶,在乙醇、二甲亚砜、二氯乙烷中微溶,在乙酸乙酯、甲苯中几乎不溶。左氧氟沙星口服后吸收完全,相对生物利用度接近100%,吸收后广泛分布至各组织、体液,在扁桃体、前列腺组织、痰液、泪液、妇女生殖道组织、皮肤和唾液等组织和体液中。
CN104288112A公开了一种盐酸左氧氟沙星片剂,其采用采用滑石粉和硬脂酸以特定的配伍比例加入,在盐酸左氧氟沙星片剂规模化生产测试中表现出优越的质量可控性,制备的盐酸左氧氟沙星片具备良好的安全有效性,但未能解决长期储存过中盐酸左氧氟沙星片易聚集,溶出度下降的趋势。
因此研制开发一种体外溶出好、稳定不下降的盐酸左氧氟沙星片迫在眉捷
发明内容
本发明的目的是提供一种新的左氧氟沙星片剂药物组合物,该药物组合物的稳定性好,溶出好。
本发明的另一个目的在于提供一种左氧氟沙星片剂药物组合物的制备方法,该方法适合工业生产。
具体而言,本发明提供了:
一种左氧氟沙星片剂组合物,包括:左氧氟沙星、填充剂、润滑剂、崩解剂、粘合剂、油酸。
所述的左氧氟沙星片剂组合物,各组分的重量比为:左氧氟沙星500重量份、填充剂40~60重量份、润滑剂1~3重量份、崩解剂4~6重量份、粘合剂适量、油酸3~5重量份。
所述左氧氟沙星为盐酸左氧氟沙星、左氧氟沙星半水合物、左氧氟沙星一水合物中的任一种,其重量份以左氧氟沙星计算。
所述的填充剂选自微晶纤维素、淀粉、山梨糖醇、甘露醇中的一种或几种。
所述的润滑剂选自微粉硅胶、滑石粉、硬脂酸镁、硬脂富马酸钠中的一种或几种。
所述的崩解剂选自羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠中的一种或几种。
所述的粘合剂为羟丙基纤维素、甘油三硬脂酸酯、甲基丙烯酸甲酯中的一种或几种。
所述的左氧氟沙星片剂组合物,各组分的重量比为:左氧氟沙星500重量份、微晶纤维素40~60重量份、硬脂富马酸钠1~3重量份、交联羧甲基纤维素钠4~6重量份、羟丙基纤维素适量、油酸3~5重量份。
所述的一种左氧氟沙星片剂组合物的制备方法,包括:
(1)将左氧氟沙星、填充剂、润滑剂、崩解剂分别过筛,备用;
(2)将油酸、粘合剂溶于乙醇中,制成粘合剂溶液;
(3)称取处方量的左氧氟沙星、填充剂和崩解剂置于流化床造粒机中,用粘合剂溶液进行喷雾造粒,干燥,再加入润滑剂混合均匀后压片,得左氧氟沙星片。
所述的左氧氟沙星片剂组合物的制备方法,还包括将步骤(3)所得的左氧氟沙星片用包衣剂包衣,得包衣片剂。
本发明与现有技术相比具有以下优点和积极效果:
1、本发明的产品稳定性好,溶出完全。
2、本发明的产品生产操作简单易行,适合于工业生产。
具体实施方式
以下通过具体实施方式的描述对本发明作进一步说明,但这并非是对本发明的限制,本领域技术人员根据本发明的基本思想,可以做出各种修改或改进,但是只要不脱离本发明的基本思想,均在本发明的范围之内。
试验方法
【含量测定】照高效液相色谱法(中国药典2015年版四部通则0512)测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂;以醋酸铵高氯酸钠溶液(取醋酸铵4.0g和高氯酸钠7.0g,加水1300ml使溶解,用磷酸调节pH值至2.2)-乙腈(85:15)流动相;检测波长为294nm。柱温为40℃。称取左氧氟沙星对照品、环丙沙星对照品和杂质E对照品各适量,加0.1mol/L盐酸溶液溶解并稀释制成每1ml中约含左氧氟沙星0.1mg、环丙沙星和杂质E各5μg的混合溶液。取10μl注入液相色谱仪,记录色谱图。
测定法取本品10片,精密称定,研细,精密称取细粉适量(约相当于左氧氟沙星,按C18H20FN3O4计0.1g),置100ml量瓶中,加0.1mol/L盐酸溶液溶解并稀释至刻度,摇匀,滤过,精密量取续滤液5ml,置50ml量瓶中,用0.1mol/L盐酸溶液稀释至刻度,摇匀,作为供试品溶液,精密量取10μl注入液相色谱仪,记录色谱图;另精密称取左氧氟沙星对照品适量,用0.1mol/L盐酸溶液溶解并定量稀释制成每1ml中含0.1mg的溶液,同法测定。按外标法以峰面积计算,即得。
【有关物质】取本品细粉适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1ml中约含左氧氟沙星(按C18H20FN3O4计)1.0mg的溶液,滤过,取续滤液作为供试品溶液;精密量取适量,用0.1mol/L盐酸溶液定量稀释制成每1ml中约含2μg的溶液,作为对照溶液。精密量取对照溶液适量,用0.1mol/L盐酸溶液定量稀释制成每1ml中约含0.2μg的溶液,作为灵敏度溶液。照高效液相色谱法(中国药典2015年版四部通则0512)测定。用十八烷基硅烷键合硅胶为填充剂;以醋酸铵高氯酸钠溶液(取醋酸铵4.0g和高氯酸钠7.0g,加水1300ml使溶解,用磷酸调节pH值至2.2)-乙腈(85:15)为流动相A,乙腈为流动相B;按下表进行线性梯度洗脱。柱温为40℃。量取灵敏度溶液10μl注入液相色谱仪,以294nm为检测波长,主成分色谱峰峰高的信噪比应大于10。再精密量取供试品溶液、对照溶液和杂质A与杂质E混合对照品溶液各10μl,分别注入液相色谱仪,以294nm为检测波长,记录色谱图。
杂质A:
杂质E:
溶出度取本品,照溶出度与释放度测定法(中国药典2015年版四部通则0931第一法),以盐酸溶液(9→1000)900ml为溶出介质,转速为100转,依法操作,经30分钟时,取溶液适量滤过,精密量取续滤液适量,用溶出介质定量稀释制成每1ml中约含左氧氟沙星(按C18H20FN3O4计)5.5μg的溶液,照紫外-可见分光光度法(中国药典2015年版四部通则0401),在294nm的波长处测定吸光度;另精密称取左氧氟沙星对照品适量,加溶出介质溶解并定量稀释制成每1ml中约含5.5μg的溶液,同法测定,计算每片的溶出量,限度为标示量80%,应符合规定。
试验例1:处方筛选试验1
取左氧氟沙星5g(含量99.9%,总杂0.09%),按下述处方(见表1)制得含有左氧氟沙星片剂,检测溶出度及有关物质,结果见表2:
表1左氧氟沙星片剂处方筛选1(单位:g)
处方1制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂酸镁、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂酸镁混合均匀后压片,得左氧氟沙星片。
处方2-4制备方法
制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂酸镁、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂酸镁混合均匀后压片,得左氧氟沙星片。
表2试验结果
结论:采用本发明处方制备的左氧氟沙星片剂中杂质的量显著低于无油酸添加的处方,但当油酸含量超过一定范围,其杂质A含量反而增多。
试验例2:处方筛选试验2
表3润滑剂筛选(单位:g)
制备方法:
(1)将左氧氟沙星、微晶纤维素、硬脂富马酸钠、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
分别对所制备的颗粒的流动性、素片的外观、脆碎度、崩解时限、溶出度等基本指标进行重点评价,以筛选出较好的处方,结果见表4。
表4润滑剂及其用量的处方评价结果
试验表明,每500重量份左氧氟沙星相对使用1~3重量份的硬脂富马酸钠作为润滑剂,即能达到很好的润滑效果,并具有较好的抗粘作用;确保本品颗粒具有较好的流动性,满足左氧氟沙星片自动化生产的要求。
试验例3:加速试验
取实施例4、5、6产品制得的产品进行加速试验,结果见表3。
表3左氧氟沙星片剂加速试验数据
包装:市售包装,考察条件:温度40℃,湿度75%
注:①本品为薄膜衣片,除去包衣后显类白色
结论:由上表可知道,按本发明方法制备的产品,在高温及光照下的稳定性较好。
制备实施例
实施例1
处方
制备方法
(1)将左氧氟沙星、山梨糖醇、硬脂富马酸钠、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、山梨糖醇和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
实施例2
处方
制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂富马酸钠、羧甲基淀粉钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和羧甲基淀粉钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
实施例3
处方
制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂富马酸钠、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
实施例4
处方
制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂富马酸钠、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
实施例5
处方
制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂富马酸钠、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
实施例6
处方
制备方法
(1)将左氧氟沙星、微晶纤维素、硬脂富马酸钠、交联羧甲基纤维素钠分别过80目筛,备用;
(2)将羟丙纤维素溶于乙醇中,制成5%(w/w)羟丙基纤维素乙醇溶液后,加入油酸其溶解;
(3)称取处方量的左氧氟沙星、微晶纤维素和交联羧甲基纤维素钠置于流化床造粒机中,用步骤(2)制得的粘合剂溶液进行喷雾造粒,干燥,再加入硬脂富马酸钠混合均匀后压片,得左氧氟沙星片。
Claims (9)
1.一种左氧氟沙星片剂组合物,包括:左氧氟沙星、填充剂、润滑剂、崩解剂、粘合剂,其特征在于,还包括油酸。
2.根据权利要求1所述的左氧氟沙星片剂组合物,其特征在于,各组分的重量比为:左氧氟沙星500重量份、填充剂40~60重量份、润滑剂1~3重量份、崩解剂4~6重量份、粘合剂适量、油酸3~5重量份。
3.根据权利要求1或2所述的左氧氟沙星片剂组合物,其特征在于,所述的填充剂选自微晶纤维素、淀粉、山梨糖醇、甘露醇中的一种或几种。
4.根据权利要求1或2所述的左氧氟沙星片剂组合物,其特征在于,所述的润滑剂选自微粉硅胶、滑石粉、硬脂酸镁、硬脂富马酸钠中的一种或几种。
5.根据权利要求1或2所述的左氧氟沙星片剂组合物,其特征在于,所述的崩解剂选自羧甲基淀粉钠、交联聚维酮、交联羧甲基纤维素钠中的一种或几种。
6.根据权利要求1或2所述的左氧氟沙星片剂组合物,其特征在于,所述的粘合剂为羟丙基纤维素、甘油三硬脂酸酯、甲基丙烯酸甲酯中的一种或几种。
7.根据权利要求2所述的左氧氟沙星片剂组合物,其特征在于,所述的组合物包括:左氧氟沙星500重量份、微晶纤维素40~60重量份、硬脂富马酸钠1~3重量份、交联羧甲基纤维素钠4~6重量份、羟丙基纤维素适量、油酸3~5重量份。
8.一种左氧氟沙星片剂组合物的制备方法,其特征在于,
(1)将左氧氟沙星、填充剂、润滑剂、崩解剂分别过筛,备用;
(2)将油酸、粘合剂溶于乙醇中,制成粘合剂溶液;
(3)称取处方量的左氧氟沙星、填充剂和崩解剂置于流化床造粒机中,用粘合剂溶液进行喷雾造粒,干燥,再加入润滑剂混合均匀后压片,得左氧氟沙星片。
9.根据权利要求8所述的左氧氟沙星片剂组合物的制备方法,其特征在于,还包括将步骤(3)所得的左氧氟沙星片用包衣剂包衣,得包衣片剂。
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