CN114099462B - 度洛西汀延迟释放药物组合物及制备方法 - Google Patents
度洛西汀延迟释放药物组合物及制备方法 Download PDFInfo
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Abstract
本发明公开了度洛西汀延迟释放药物组合物及制备方法,药物组合物包括含度洛西汀或其盐的丸芯及包覆在丸芯上的肠溶层,其中肠溶层包括醋酸纤维素苯三酸酯、增塑剂,增塑剂为甘油或甘油的混合物,基于偶然的发现,以醋酸纤维素苯三酸酯与甘油类增塑剂制备的肠溶液对度洛西汀或其盐的惰性丸芯进行包衣后制备的药物在溶出性能上与原研剂基本相同,性能优异、溶出稳定,且肠溶液的制备过程无需氨水中和,药物成型工艺再度简化且稳定性提升,成品率提高,相对降低成本,有助提升产品的竞争力。
Description
技术领域
本发明涉及药物技术领域,具体涉及度洛西汀延迟释放药物组合物及制备方法。
背景技术
度洛西汀在化学上是(+)-(S)-N-甲基-γ-(1-萘氧基)-2-噻吩丙胺,通常用作其盐酸盐,是一种选择性血清素和去甲肾上腺素再摄取抑制剂(SSNRI),对重度抑郁症有效,在广泛性焦虑症中一样有效。
度洛西汀可作为包含延迟释放小丸的胶囊在美国以商品名CYMBALTA TM商购。它已被FDA批准用于治疗重度抑郁症、广泛性焦虑症、治疗与糖尿病周围神经病变相关的神经性疼痛和治疗纤维肌痛。度洛西汀也可在欧洲以商品名CYMBALTATM和YENTREVETM的形式作为硬胃抗性胶囊商购获得。它已被欧洲、中东和非洲批准用于治疗重度抑郁症、治疗成人糖尿病周围神经性疼痛和治疗广泛性焦虑症,并用于治疗女性中度至重度压力性尿失禁。
度洛西汀是一种酸不稳定物质,在胃的酸性环境中非常容易降解。因此度洛西汀被制备成肠溶包衣剂型以防止其被酸降解。美国专利第5,508,276号公开了一种包含羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)作为肠溶包衣聚合物的肠溶度洛西汀小丸。该专利还公开了HPMCAS应该被中和,例如,用浓氨溶液来促进其溶解。并且该专利还公开了度洛西汀被发现与许多肠溶衣反应形成缓慢溶解或不溶性的包衣。这可能导致药物释放特性不佳和/或生物利用度低。
美国专利申请号2007/0292511公开了一种盐酸度洛西汀缓释制剂,其包含惰性丸芯、包含度洛西汀盐酸盐的药物层、隔离层和包含甲基丙烯酸共聚物和邻苯二甲酸羟丙基甲基纤维素中的至少一种的肠溶层。
美国专利申请号2008/0226711公开了一种延迟释放药物组合物,其包含丸芯,该丸芯包含用度洛西汀包衣的惰性丸芯,任选地在丸芯上的隔离衣和在丸芯上或隔离衣上的肠溶衣,其中肠溶衣包含邻苯二甲酸羟丙基甲基纤维素(HPMCP))或醋酸邻苯二甲酸纤维素(CAP)或聚醋酸乙烯邻苯二甲酸酯(PVAP)。
检索到的现有技术中均未发现醋酸纤维素苯三酸酯(CAT)在度洛西汀肠溶层中的应用,此外CAT、HPMCAS等在现有技术中多需要氨中和,但氨中和的程度需准确控制,其极易对溶出造成大的影响,导致成品率的降低,成型难度大。
对此本司拟寻找新的途径将醋酸纤维素苯三酸酯应用至度洛西汀的肠溶层中,提高溶出性能,降低成型难度,提高成品率。
发明内容
为解决上述至少一个技术缺陷,本发明提供了如下技术方案:
本申请文件公开度洛西汀延迟释放药物组合物,包括含度洛西汀或其盐的丸芯及包覆在丸芯上的肠溶层,其中肠溶层包括醋酸纤维素苯三酸酯、增塑剂,增塑剂为甘油或甘油的混合物。
基于偶然的发现,以醋酸纤维素苯三酸酯与甘油类增塑剂制备的肠溶液对度洛西汀或其盐的惰性丸芯进行包衣后制备的药物在溶出性能上与原研剂基本相同,性能优异、溶出稳定,且肠溶液的制备过程无需氨水中和,药物成型工艺再度简化且稳定性提升,成品率提高,相对降低成本,有助提升产品的竞争力。
进一步,以质量计,醋酸纤维素苯三酸酯占比组合物的比例:5-40%,所述丸芯占比组合物的比例:10-50%,如醋酸纤维素苯三酸酯占比组合物的比例为5%,10%,15%,20%,30%,40%等,丸芯占比组合物的比例为10%,20%,30%,35%,40%,45%,50%等。
进一步,所述肠溶层中增塑剂为甘油、抗粘剂及溶剂的混合物,所述溶剂为水或醇,无需氨水中和即可制备肠衣,抗粘剂优选滑石粉。
进一步,所述丸芯中包括赋形剂,赋形剂包括稀释剂、崩解剂、粘合剂、润滑剂、助流剂、增塑剂、抗粘剂或遮光剂中一种或多种。
进一步,所述药学惰性丸芯为蔗糖丸芯或微晶纤维素丸芯,粘合剂为羟丙基纤维素、玉米淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟乙基纤维素或预胶化淀粉中一种或多种,所述崩解剂为交联羧甲基纤维素钠、交聚维酮、羟基乙酸淀粉钠或低取代羟丙基纤维素中一种或多种。优选,其中抗粘剂为滑石粉,崩解剂为交联聚维酮或交联羧甲基纤维素钠,所述粘合剂为羟丙基甲基纤维素。
进一步,在所述丸芯上依次包覆隔离层、肠溶层、修饰层,以质量计,所述丸芯占比组合物的比例为10-50%,所述肠溶层占比组合物的比例为5-30%,所述隔离层占比组合物的比例为5-35%,隔离层的作用是为肠溶层的应用提供平滑的基础,延长微丸对酸性条件的抵抗力并提高稳定性,可根据药物的所需性能自由选择。可选的比例如:组合物中,丸芯占比40%,隔离层占比20%,肠溶层占比25%,修饰层占比15%,或者丸芯占比30%,隔离层占比30%,肠溶层占比25%,修饰层占比15%,或丸芯占比50%,隔离层占比20%,肠溶层占比15%,修饰层占比10%等。
进一步,以度洛西汀或其盐为活性成分,辅以药学惰性丸芯、赋形剂制成丸芯,以质量计,所述丸芯中组分比例:15-40%的度洛西汀或其盐、30-80%的蔗糖丸芯、2-10%的羟丙基甲基纤维素粘合剂、0-10%的羟丙基纤维素、0-10%的蔗糖细粒、1-10%的崩解剂和1-10%的抗粘剂。可选择的比例如:
丸芯中组分比例:40%的度洛西汀或其盐、40%的蔗糖丸芯、8%的羟丙基甲基纤维素粘合剂、6%的崩解剂和6%的抗粘剂。
丸芯中组分比例:30%的度洛西汀或其盐、50%的蔗糖丸芯、8%的羟丙基甲基纤维素粘合剂、6%的崩解剂和6%的抗粘剂。
丸芯中组分比例:30%的度洛西汀或其盐、50%的蔗糖丸芯、5%的羟丙基甲基纤维素粘合剂、9%的崩解剂和6%的抗粘剂。
丸芯中组分比例:25%的度洛西汀或其盐、65%的蔗糖丸芯、3%的羟丙基甲基纤维素粘合剂、3%的崩解剂和4%的抗粘剂。
其中抗粘剂优选滑石粉,崩解剂优选交联聚维酮或交联羧甲基纤维素钠。
进一步,所述隔离层包括蔗糖、羟丙基甲基纤维素和滑石粉,以质量计,所述隔离层中蔗糖、羟丙基甲基纤维素和滑石粉的比例为1:0.5:0.1。
本申请文件公开度洛西汀延迟释放药物组合物的制备方法,包括以下步骤:
将醋酸纤维素苯三酸酯、甘油或甘油的混合物相混合形成肠溶液的步骤;
以肠溶液对含度洛西汀或其盐的惰性丸芯进行包衣形成肠溶层的步骤。
本方案的制备过程中,无需氨水中和肠溶液,工艺难度降低,稳定性提升,药物的成品率提升。
进一步,将醋酸纤维素苯三酸酯溶于异丙醇-丙酮溶液中形成混悬液,将甘油溶于异丙醇-丙酮溶液并加入滑石粉形成甘油混合物,将甘油混合物与酸纤维素苯三酸酯的混悬液相混形成肠溶液,无需氨水中和。
与现有技术相比,本发明的有益效果:
1、本发明基于偶然将醋酸纤维素苯三酸酯应用在度洛西汀的肠衣上,并惊奇发现以醋酸纤维素苯三酸酯与甘油增塑剂制备肠溶层,性能稳定,无需氨水中和,成型的药品溶出曲线优异,本方案降低了药品制备难度,提高了成品率,产品竞争力提升。
附图说明
图1是不同浓度氨水中和后肠溶液图;
图2是肠溶液加热后出现的果冻状物质图;
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明。
一、制备
实施例1
依据表1中处方-F2中组分比例制备度洛西汀延迟释放药物组合物,步骤如下:
丸芯的制备:1.将羟丙基甲基纤维素溶于水(配成4%溶液),制成羟丙基甲基纤维素溶液。
2.羟丙基甲基纤维素溶液澄清后,将盐酸度洛西汀原料药加入HPMC溶液中。
3.度洛西汀原料药充分分散后加入滑石粉。
4.将蔗糖丸芯预热至46℃,以步骤3中溶液对蔗糖惰性丸芯进行包衣。
5.烘干,温度60℃,冷却后,出料。
隔离层的制备:
1.将羟丙基甲基纤维素溶于水(配成5%溶液),制成羟丙基甲基纤维素溶液。
2.待羟丙基甲基纤维素溶液澄清后,将蔗糖加入羟丙基甲基纤维素溶液中。
3.待蔗糖充分分散后加入滑石粉。
4.以步骤3中溶液对制备的丸芯进行包衣。
5.烘干,温度60℃,冷却后,出料。
肠溶层的制备:1.将醋酸纤维素苯三酸酯溶解于异丙醇-丙酮溶液中(配成7%溶液),按异丙醇50%:50%丙酮的质量比例混合成异丙醇-丙酮溶液。
2.在异丙醇-丙酮混合液中加入甘油(比例20%),调成溶液。
3.在甘油溶液中加入滑石粉。
4.将滑石粉和甘油的混合溶液加入步骤1制备的醋酸纤维素苯三酸酯混悬液中。
5.以步骤4制备的混合液对包覆隔离层的丸芯进行包衣。
6.烘干,温度60℃,冷却后,出料。
修饰层的制备:1.将欧巴代2分散于水中(配成15%溶液),使其形成混悬液。
2.以欧巴代2的溶液对包覆有肠溶层的丸芯进行包衣。
3、烘干,温度60℃,冷却后,出料。
并设置对比例,对比例中药物组合物的组分比例如表1中处方-F1所示,步骤与实施例1的区别如下:
肠溶层的制备:1.将氨和柠檬酸三乙酯溶解在水形成溶液(2%的溶液),使其分散良好。
2.加入醋酸羟丙基甲基纤维素琥珀酸酯并制成溶液。
3.醋酸羟丙基甲基纤维素琥珀酸酯充分溶解后加入滑石粉。
6.对包覆隔离层后丸芯进行包衣。
7.烘干,温度60℃,冷却后出料。
表1
二、测试
对实施例及对比例制备的药物制剂进行溶出测试,如下:
1、0.1N HCl 2小时,然后加入pH 6.8磷酸盐缓冲液,溶出结果如表2所示。
表2
2、0.1N HCl 2小时,然后加入pH 6.0磷酸盐缓冲液,溶出结果如表3所示。
表3
3、0.1N HCl 2小时,然后是pH 5.5的醋酸盐缓冲液,溶出结果如表4所示。
表4
4、pH 4.5醋酸缓冲液2小时,然后是pH 6.8磷酸盐缓冲液,溶出结果如表5所示。
表5
三、稳定性测试
针对对比例,设计肠溶层包衣液pH制从低中和到高中和的实验,如表6所示。
表6
如图1所示,左图为同时加入HPMCAS和不同量氨水的肠溶液,右图为加入氨水2小时后加入HPMCAS的肠溶液,从图2可以看出,用15%氨水的HPMCAS溶液在40℃加热4小时的pH计上出现果冻状物质,该温度通常是肠溶层包衣液配置过程中的配制罐温度,加热后的溶液会像果冻状物质,存在包衣风险。
实施例1中以醋酸纤维素苯三酸酯与甘油混合物作为肠溶液,在40℃加热4小时后,溶液性状稳定。
四、结论
根据以上实验可以发现处方1,醋酸羟丙基甲基纤维素琥珀酸酯不同中和水平的pH值结果各不相同,存在很多与原研生产过程中声称的氨中和过程相关的问题。不正确的中和易导致劣质产品,批次与批次之间氨中和的显着差异导致批次可变性,成型工艺难度大,成品率较低,且从溶出测试可以看出其与原研药差异大。
本方案中无需氨水中和,肠溶层性能稳定,成型工艺简单稳健,且从溶出测试可以看出其接近原研药。
以上仅是本发明的优选实施方式,本发明的保护范围并不仅局限于上述实施例,凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理前提下的若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.度洛西汀延迟释放药物组合物,其特征在于,包括含度洛西汀或其盐的丸芯及包覆在丸芯上的肠溶层,其中肠溶层包括醋酸纤维素苯三酸酯、增塑剂,增塑剂为甘油或甘油的混合物;
以质量计,醋酸纤维素苯三酸酯占比组合物的比例:5-40%,所述丸芯占比组合物的比例:10-50%;
所述丸芯中包括赋形剂,赋形剂包括稀释剂、崩解剂、粘合剂、润滑剂、助流剂、增塑剂、抗粘剂或遮光剂中一种或多种;
丸芯为蔗糖丸芯或微晶纤维素丸芯。
2.如权利要求1所述的度洛西汀延迟释放药物组合物,其特征在于:所述肠溶层中增塑剂为甘油、抗粘剂及溶剂的混合物,所述溶剂为水或醇。
3.如权利要求1所述的度洛西汀延迟释放药物组合物,其特征在于:粘合剂为羟丙基纤维素、玉米淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟乙基纤维素或预胶化淀粉中一种或多种,所述崩解剂为交联羧甲基纤维素钠、交聚维酮、羟基乙酸淀粉钠或低取代羟丙基纤维素中一种或多种。
4.如权利要求1-3任一项所述的度洛西汀延迟释放药物组合物,其特征在于:在所述丸芯上依次包覆隔离层、肠溶层、修饰层,以质量计,所述丸芯占比组合物的比例为10-50%,所述肠溶层占比组合物的比例为5-30%,所述隔离层占比组合物的比例为5-35%。
5.如权利要求4所述的度洛西汀延迟释放药物组合物,其特征在于:以度洛西汀或其盐为活性成分,辅以药学惰性丸芯、赋形剂制成丸芯,以质量计,所述丸芯中组分比例:15-40%的度洛西汀或其盐、30-80%的蔗糖丸芯、2-10%的羟丙基甲基纤维素粘合剂、0-10%的羟丙基纤维素、0-10%的蔗糖细粒、1-10%的崩解剂和1-10%的抗粘剂。
6.如权利要求4所述的度洛西汀延迟释放药物组合物,其特征在于:所述隔离层包括蔗糖、羟丙基甲基纤维素和滑石粉,以质量计,所述隔离层中蔗糖、羟丙基甲基纤维素和滑石粉的比例为1:0.5:0.1。
7.如权利要求1-6任一项所述的度洛西汀延迟释放药物组合物的制备方法,其特征在于,包括以下步骤:
将醋酸纤维素苯三酸酯、甘油或甘油的混合物相混合形成肠溶液的步骤;
以肠溶液对含度洛西汀或其盐的惰性丸芯进行包衣形成肠溶层的步骤。
8.如权利要求7所述的度洛西汀延迟释放药物组合物的制备方法,其特征在于:将醋酸纤维素苯三酸酯溶于异丙醇-丙酮溶液中形成混悬液,将甘油溶于异丙醇-丙酮溶液并加入滑石粉形成甘油混合物,将甘油混合物与酸纤维素苯三酸酯的混悬液相混形成肠溶液。
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