CN107865825B - 一种卢立康唑外用喷雾剂药物组合物及其制备方法 - Google Patents
一种卢立康唑外用喷雾剂药物组合物及其制备方法 Download PDFInfo
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Abstract
本发明提供了一种卢立康唑外用喷雾剂药物组合物及其制备方法。所述组合物包含卢立康唑、中链脂肪酸甘油酯、聚乙二醇、稳定剂、磷酸、无水乙醇。本发明组合物辅料组成简单，制备工艺简便易行，无需易燃易爆的甲乙酮作稳定剂，制得的组合物稳定性好，卢立康唑酰胺杂质可控制在很低的范围内，显著提高了产品质量。
Description
技术领域
本发明涉及一种卢立康唑外用喷雾剂药物组合物及其制备方法，属于医药技术领域。
背景技术
真菌性皮肤病是皮肤组织部位真菌感染的结果。真菌感染部位可分布于全身皮肤，发病最高的为角质层，其典型代表病症为癣病、念珠菌感染及白癜风。调查显示，皮肤真菌感染患者占皮肤科门诊患者的13％左右，其中包括88.0％的癣病患者、8.5％的念珠菌感染患者和3.4％的白癜风患者，癣病中又有64.0％为足癣。
癣病是一种难治性皮肤疾病，包括足癣、体癣、股癣等，病程缓慢，愈后复发率较高，发病时炎症较为明显，并有水疱、鳞屑及结痂等皮损现象，常伴有不同程度的瘙痒，严重影响人们的生活质量。主要致病菌有红色毛癣菌、须癣毛癣菌、絮状表皮癣菌等。足癣俗称“脚气”，是皮肤癣菌病中发病率最高的一种，红色毛癣菌是其最常见的致病菌。体癣、股癣合称体股癣，发病率仅低于足癣，主要由红色毛癣菌、须癣毛癣菌和絮状表皮癣菌所致。足癣还具有传染性，是手癣、体癣、股癣和甲癣患病重要根源。
目前，癣病治疗药物主要有两大类：第一类丙烯胺类药物，如特比萘芬、布替萘芬和萘替芬等，它们是通过抑制角鲨烯环化酶，造成麦角固醇的缺乏和角鲨烯的蓄积，从而起到杀菌作用的抗真菌药物。第二类咪唑类(imidazoles)药物，如咪康唑、益康唑、克霉唑、酮康唑和联苯苄唑。它们是一类合成的抗真菌药物，能选择性抑制真菌细胞羊毛甾醇14α-去甲基酶活性，阻止细胞膜麦角固醇合成，使细胞膜通透性改变，导致胞内重要物质丢失而使真菌死亡。咪唑类抗真菌药物是目前临床上最常用的一类治疗癣病药品，临床应用非常广泛。
卢立康唑(结构式如下式Ⅰ所示)是一种新型的咪唑类外用抗真菌药物，为拉诺康唑类似物，由日本农药株式会社(Nihon Nohyaku Co.，Ltd.)开发。2005年4月卢立康唑乳膏及洗剂在日本获批上市，商品名为
2010年、2012年分别在印度和中国上市；2013年在美国上市，商品名
除了用于治疗足癣、股癣和体癣外，卢立康唑还被开发用于甲癣(灰指甲)治疗。与通常的抗真菌外用药相比，卢立康唑具有皮肤贮留性好、抗菌谱广、抗菌活性强等优点，因此其用药周期短(为一般药物的一半)、疗效好且不易复发，故具有很强的竞争力。
但是，由于卢立康唑分子结构中的氰基较不稳定，在一定条件下易被水解为酰胺基团，形成卢立康唑酰胺形式的杂质(如下式Ⅱ所示)，影响了卢立康唑制剂的质量。上市产品未对该杂质进行控制。
CN104619320A提供了控制与含有卢立康唑的药物组合物相关的所形成的酰胺形式的形成量的方法，该组合物含有卢立康唑和选自以下的一种或多种组分：羧酸及其衍生物、酮(主要选自甲乙酮和丙酮)、磷酸及其衍生物、局部麻醉药、抗组胺剂和基于POE的非离子型表面活性剂；其中在60℃储存3周或在40℃储存6个月后，卢立康唑的酰胺衍生物的含量相对于卢立康唑的加入量按质量计不超过0.2％。但其中所用甲乙酮、丙酮属于易燃易爆化学物品，不利于工业化生产；而且甲乙酮属于易制毒-3类化学品，受管制；同时，甲乙酮对皮肤具有刺激性，不宜用于外用制剂的制备。而WO2003105841A1、CN101820877A、CN102395274A、CN102387785A、CN102481286A、CN103957907A等均采用了甲乙酮(或丙酮)来制备卢立康唑外用制剂。
CN104662017A中提及，其所提供的卢立康唑制剂能够在加速条件或更严格的条件下，例如在60℃储存3周，将酰胺形式抑制到按质量计不超过1％，更优不超过0.5％，以及更加优选不超过0.1％。但其并未给出有区别于卢立康唑制剂现有技术的其它特别的技术信息。
因此，开发一种不含甲乙酮同时又能很好地控制卢立康唑酰胺杂质的卢立康唑外用制剂，是本领域亟需解决的问题。
发明内容
为了克服上述现有技术的不足，本发明提供一种辅料组成简单且不含甲乙酮、成本低廉、制备工艺简便、酰胺杂质含量极低的卢立康唑外用喷雾剂药物组合物及其制备方法。
本发明是通过如下技术方案实现的：
该卢立康唑外用喷雾剂药物组合物，包含卢立康唑、中链脂肪酸甘油酯、聚乙二醇、稳定剂、无水乙醇和磷酸。
进一步地，所述中链脂肪酸甘油酯为C8～C12脂肪酸的甘油一酯、二酯或三酯中的一种或多种的混合物。
进一步地，所述聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇800、聚乙二醇1000、聚乙二醇1500、聚乙二醇2000、聚乙二醇4000、聚乙二醇6000中的一种或多种的混合物。
进一步地，所述稳定剂选自丁基羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、消旋α-生育酚中的一种或多种的混合物。
更进一步地，所述组合物每100mL包含：
其中所述中链脂肪酸甘油酯为C8～C12脂肪酸的甘油一酯、二酯或三酯中的一种或多种的混合物，所述聚乙二醇选自聚乙二醇200、聚乙二醇300、聚乙二醇400、聚乙二醇600、聚乙二醇800、聚乙二醇1000、聚乙二醇1500、聚乙二醇2000、聚乙二醇4000、聚乙二醇6000中的一种或多种的混合物，所述稳定剂为丁基羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯、消旋α-生育酚中的一种或多种的混合物。
在一实施方案中，所述组合物每100mL包含：
在一实施方案中，所述组合物每100mL包含：
在一实施方案中，所述组合物每100mL包含：
在一实施方案中，所述组合物每100mL包含：
进一步地，本发明卢立康唑外用喷雾剂药物组合物每100mL还包含防腐剂2～5g，其中所述防腐剂选自卡松、苯甲醇或二者的混合物。
本发明还提供该卢立康唑外用喷雾剂药物组合物的制备方法，包括以下步骤：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入稳定剂、磷酸、中链脂肪酸甘油酯和聚乙二醇，再补加入剩余约20％的无水乙醇至规定体积，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装轧口得成品。
若组合物进一步包含防腐剂，其制备步骤为：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入稳定剂、磷酸、防腐剂、中链脂肪酸甘油酯和聚乙二醇，再补加入剩余约20％的无水乙醇至规定体积，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装轧口得成品。
本发明卢立康唑外用喷雾剂及其制备方法具有以下优点：
(1)药物稳定性好，加速试验中，卢立康唑酰胺杂质含量极低，大大低于0.1％(0.002％～0.008％)，Z异构体杂质含量低于0.1％，SE异构体杂质含量在1％以下。
(2)优选出消旋α-生育酚等作稳定剂，很好地抑制了卢立康唑酰胺杂质的产生，不但取代现有技术中使用甲乙酮这一类不利于安全生产且有皮肤刺激性的化学品，而且其制剂产品中卢立康唑酰胺杂质含量也大大降低，提高了产品质量。
(3)与现有技术相比，本发明药物组合物采用的辅料组成更简单，制备工艺更简便易行。
(4)增加了卢立康唑喷雾剂这一新的外用剂型，进一步满足了临床需求，提高了患者对药物的顺应性。
具体实施方式
下面将通过实施例对本发明作进一步的描述，这些描述并不是对本发明内容作进一步的限定。本领域的技术人员应理解，对本发明内容所作的等同替换，或相应的改进，仍属于本发明的保护范围之内。
实施例1卢立康唑外用喷雾剂的制备
处方：
制备方法：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入没食子酸丙酯、磷酸、中链脂肪酸甘油三酯和聚乙二醇300，再补加入剩余约20％的无水乙醇至1000mL，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装100瓶，轧口得成品。
实施例2卢立康唑外用喷雾剂的制备
处方：
制备方法：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入二丁基羟基甲苯、磷酸、中链脂肪酸甘油三酯和聚乙二醇400，再补加入剩余约20％的无水乙醇至1000mL，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装100瓶，轧口得成品。
实施例3卢立康唑外用喷雾剂的制备
处方：
制备方法：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入消旋α-生育酚、磷酸、中链脂肪酸甘油三酯和聚乙二醇400，再补加入剩余约20％的无水乙醇至1000mL，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装100瓶，轧口得成品。
实施例4卢立康唑外用喷雾剂的制备
处方：
制备方法：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入消旋α-生育酚、磷酸、苯甲醇、中链脂肪酸甘油三酯和聚乙二醇400，再补加入剩余约20％的无水乙醇至1000mL，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装100瓶，轧口得成品。
实施例5卢立康唑外用喷雾剂的制备
处方：
制备方法：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入丁基羟基茴香醚、磷酸、卡松、中链脂肪酸甘油三酯和聚乙二醇200，再补加入剩余约20％的无水乙醇至1000mL，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装100瓶，轧口得成品。
实施例6卢立康唑外用喷雾剂的制备
处方：
制备方法：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入二丁基羟基甲苯、磷酸、中链脂肪酸甘油三酯和聚乙二醇6000，再补加入剩余约20％的无水乙醇至1000mL，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装100瓶，轧口得成品。
实施例7稳定性考察(加速试验)
(1)模拟市售包装将实施例1、3、5制得的样品置于温度60℃下放置3周，检测各有关物质，结果见下表1：
表1 60℃下3周有关物质考察
(2)模拟市售包装将实施例1、3、5制得的样品置于温度40℃下放置6个月，检测各有关物质，结果见下表2：
表2 40℃下6个月有关物质考察
由表1、表2可见，在加速试验中，三个实施例样品40℃下6个月均未检出卢立康唑酰胺杂质，三样品60℃下3周检测到该酰胺杂质含量最高为0.008％，最低为0.002％，大大低于同等条件下CN104619320A中的0.2％和CN104662017A中的0.1％；其Z异构体杂质含量低于0.1％，SE异构体杂质含量在1％以下，符合质量要求；其它最大单杂含量、除异构体外总杂含量均在规定范围内，符合要求。
Claims (2)
1.一种卢立康唑外用喷雾剂药物组合物，其特征在于，所述组合物每100mL包含：
2.权利要求1所述药物组合物的制备方法，其特征在于包括以下步骤：
(1)按处方量称取各原辅料；
(2)向配液罐中先加入约80％的无水乙醇，开启搅拌器，依次加入没食子酸丙酯、磷酸、中链脂肪酸甘油酯和聚乙二醇300，再补加入剩余约20％的无水乙醇至规定体积，搅拌均匀；
(3)加入卢立康唑，搅拌溶解；
(4)将药液用3μm聚丙烯滤芯过滤；
(5)按10mL/瓶灌装轧口得成品。
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