CN115487198A - 一种快溶出度的左炔诺孕酮制剂及其制备方法 - Google Patents
一种快溶出度的左炔诺孕酮制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种快溶出度的左炔诺孕酮制剂及其制备方法，所述制剂的原料包括：左炔诺孕酮1～2份、一水乳糖32～74份、玉米淀粉20～35份、二氧化硅0.5～4份、羧甲淀粉钠1～6份、硬脂酸镁0.2～2份、十二烷基硫酸钠0.2～2份、羟丙甲纤维素0.2～2份、聚维酮0.2～2份，按重量份计。基于上述配比结合本发明提供的制备方法，能显著提升左炔诺孕酮制剂的溶出速度，进而提高左炔诺孕酮的生物利用度。
Description
技术领域
本发明属于制药技术领域，具体涉及一种快溶出度的左炔诺孕酮制剂及其制备方法。
背景技术
左炔诺孕酮的化学名称为(-)-13-乙基-17-羟基-18,19-双去甲基-17α-孕甾-4-烯-20-炔-3-酮，英文名Levonorgestrel。左炔诺孕酮作为一种速效、短效口服避孕药，其避孕机制是显著抑制排卵和阻止孕卵着床，并使宫颈黏液稠度增加，精子穿透阻力增大，从而发挥速效避孕作用。左炔诺孕酮也可用于治疗月经不调，子宫功能性出血及子宫内膜异位症等。
左炔诺孕酮一般通过口服给药，但是该药物为难溶性药物，不溶于水、乙醇、异丙醇、丙酮、乙酸乙酯等溶剂；而且，现有方法制备的左炔诺孕酮片剂通常存在下列问题：药物吸收差、溶出度低、生物利用度低、事后紧急避孕效果差等。因此，为了保证事后紧急避孕药的效果，通常采取增加剂量的办法，但高剂量引发较多的不良反应。
为提高溶出，通常采用微粉化原料、制备固体分散体、加入有机溶剂等方式。将原料微粉化处理后，左炔诺孕酮片1小时的溶出度约为60％，提高了生物利用度；但微粉化技术对设备有特殊要求，粉尘暴露时间长，环境和职业的安全性受到威胁。固体分散体存在药物老化的现象，药物贮存不稳定，难以保证药品质量。加入有机溶剂能够增加药物溶出度，但是有机溶剂对人体有害，因此需严格控制残留。
发明内容
有鉴于此，本发明的目的在于提供一种具有快溶出度的左炔诺孕酮制剂及其制备方法，所得左炔诺孕酮制剂能够迅速的溶出释放，生物利用度高。
本发明的技术方案具体如下：
一种快溶出度的左炔诺孕酮制剂，包括：左炔诺孕酮1～2份、一水乳糖32～74份、玉米淀粉20～35份、二氧化硅0.5～4份、羧甲淀粉钠1～6份、硬脂酸镁0.2～2份、十二烷基硫酸钠0.2～2份、羟丙甲纤维素0.2～2份、聚维酮0.2～2份，按重量份计。
在上述技术方案中，左炔诺孕酮制剂的优选组成为：左炔诺孕酮1份或2份、一水乳糖44.6份、玉米淀粉33.7份、二氧化硅1.9份、羧甲淀粉钠3.9份、硬脂酸镁0.6份、十二烷基硫酸钠0.3份、羟丙甲纤维素0.5份、聚维酮0.8份，按重量份计。
在上述技术方案中，左炔诺孕酮制剂可以为片剂、胶囊剂、丸剂、颗粒剂或散剂。
本发明进一步提供了制备上述快溶出度的左炔诺孕酮制剂的方法，包括以下步骤：
S1、取全部的左炔诺孕酮与一水乳糖等量混合均匀后过筛(将筛上物破碎使其全部过筛)，再将筛下物与一水乳糖等量混合均匀过筛(将筛上物破碎使其全部过筛)，重复该操作3～6次得到母粉；
S2、将十二烷基硫酸钠、羟丙甲纤维素、聚维酮加入溶剂中并搅散泡发；
S3、向母粉中加入剩余的一水乳糖、玉米淀粉以及部分二氧化硅和羧甲淀粉钠，混合均匀后加入步骤S2所得溶液，混匀干燥制粒后，再加入硬脂酸镁和剩余的二氧化硅、羧甲淀粉钠成型。
在上述技术方案中，左炔诺孕酮的粒径条件为：99％及以上过80目筛网，一水乳糖的粒径条件为：99％及以上过100目筛网；基于此，步骤S1过筛操作时所用筛网的目数可以为80～120目；最佳地，筛网目数为80目。
在上述技术方案中，步骤S2所用溶剂优选为30wt％的乙醇水溶液，且溶剂加入量为25～28份。
在上述技术方案中，步骤S2所述搅散泡发的时间大于5h，优选为5～10h。
本发明的有益效果为：本发明通过改良配方及制备方法，生产的左炔诺孕酮制剂的溶出速度得到了显著提升，活性物质损耗小，有效提高了生物利用度。
附图说明
图1为各实施例和对比例制备的左炔诺孕酮片剂的溶出速度对比图。
具体实施方式
下面将结合实施例，对本发明的技术方案进行清楚、完整地描述。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
下述实施例中，若无特殊说明，均为常规方法；所述试剂和材料，若无特殊说明，均可从商业途径获得。
实施例1
本例中的左炔诺孕酮制剂的配方具体为：按重量份计，左炔诺孕酮2份、一水乳糖64.4份、玉米淀粉25.7份、二氧化硅1.9份、羧甲淀粉钠3.9份、硬脂酸镁0.6份、十二烷基硫酸钠0.3份、羟丙甲纤维素0.5份、聚维酮0.8份。
本例中的左炔诺孕酮制剂的制备过程如下所示：
(1)活性物质前处理：按处方称取2份的左炔诺孕酮，按1:1的质量比例将左炔诺孕酮与一水乳糖混合均匀，过80目筛，筛上物用机械挤压使其破碎后过筛；再将混合过筛后的筛下物按1:1的质量比例与一水乳糖混合均匀，过80目筛，筛上物用机械挤压使其破碎后过筛；重复上述混合、过筛步骤4次，得到母粉。
(2)将十二烷基硫酸钠、羟丙甲纤维素、聚维酮加入27份30wt％乙醇水溶液中，搅散泡发，且泡发时间10h。
(3)在母粉中加入剩余的一水乳糖、全部的玉米淀粉以及50％的二氧化硅和50％的羧甲淀粉钠混合均匀，加入(2)中泡发的溶液，混匀、干燥、制粒，再加入硬脂酸镁以及剩余量的羧甲淀粉钠、二氧化硅分别作润滑剂、崩解剂、助流剂混匀后制成片剂，所得片剂直径为5.5～6.0mm，硬度为3～4.5kg。
本例制备的左炔诺孕酮片的规格为1.5mg/片。
实施例2
本例中的左炔诺孕酮制剂的配方具体为：按重量份计，左炔诺孕酮1份、一水乳糖64.4份、玉米淀粉25.7份、二氧化硅1.9份、羧甲淀粉钠3.9份、硬脂酸镁0.6份、十二烷基硫酸钠0.3份、羟丙甲纤维素0.5份、聚维酮0.8份。
本例中的左炔诺孕酮制剂的制备过程如下所示：
(1)活性物质前处理：按处方称取1份左炔诺孕酮，按1:1的质量比例与一水乳糖混合均匀，过80目筛，筛上物用机械挤压使其破碎后过筛；再将混合过筛后的筛下物按1:1的质量比例与一水乳糖混合均匀，过80目筛，筛上物用机械挤压使其破碎后过筛；重复上述混合、过筛步骤4次，得到母粉。
(2)将十二烷基硫酸钠、羟丙甲纤维素、聚维酮加入27份30wt％乙醇水溶液中，搅散泡发，且泡发时间10h。
(3)在母粉中加入剩余的一水乳糖、全部玉米淀粉以及50％的二氧化硅和50％的羧甲淀粉钠混合均匀，加入(2)中泡发的溶液，混匀、干燥、制粒，再加入硬脂酸镁以及剩余量的羧甲淀粉钠、二氧化硅分别作润滑剂、崩解剂、助流剂混匀后制成片剂，所得片剂直径为5.5～6.0mm，硬度为3～4.5kg。
本例制备的左炔诺孕酮片的规格为0.75mg/片。
对比例1
本例与实施例1不同之处在于，用相同粒度条件的蔗糖替换一水乳糖，其余原料及制备方法均与实施例1一致。
对比例2
本例中的左炔诺孕酮制剂的配方与实施例1一致。
本例中的左炔诺孕酮制剂的制备过程如下所示：
(1)将十二烷基硫酸钠、羟丙甲纤维素、聚维酮加入27份30wt％乙醇水溶液中，搅散泡发，且泡发时间10h。
(2)将左炔诺孕酮、一水乳糖、玉米淀粉以及50％的二氧化硅和50％的羧甲淀粉钠混合均匀，加入(1)中泡发的溶液，混匀、干燥、制粒，再加入硬脂酸镁以及剩余量的羧甲淀粉钠、二氧化硅分别作润滑剂、崩解剂、助流剂混匀后制成片剂，所得片剂直径为5.5～6.0mm，硬度为3～4.5kg。
对比例3
本例中的左炔诺孕酮制剂的配方与实施例1一致。
本例中的左炔诺孕酮制剂的制备过程如下所示：
(1)活性物质前处理：按处方称取2份的左炔诺孕酮，按1:1的质量比例将左炔诺孕酮与一水乳糖混合均匀，过80目筛，筛上物用机械挤压使其破碎后过筛；再将混合过筛后的筛下物按1:1的质量比例与一水乳糖混合均匀，过80目筛，筛上物用机械挤压使其破碎后过筛；得到母粉。
(2)将十二烷基硫酸钠、羟丙甲纤维素、聚维酮加入27份30wt％乙醇水溶液中，搅散泡发，且泡发时间10h。
(3)在母粉中加入一水乳糖、玉米淀粉以及50％的二氧化硅和50％的羧甲淀粉钠混合均匀，加入(2)中泡发的溶液，混匀、干燥、制粒，再加入硬脂酸镁以及剩余量的羧甲淀粉钠、二氧化硅分别作润滑剂、崩解剂、助流剂混匀后制成片剂，所得片剂直径为5.5～6.0mm，硬度为3～4.5kg。
对上述各实施例和对比例制备的左炔诺孕酮片剂进行溶出度测定，测定方法参照BP质量标准(岛津和福克斯J20-06色谱柱)，检测结果如下表和图1所示：
从上表可知，本发明实施例制备的左炔诺孕酮制剂的溶出速度显著提升。
以上所述是本发明的优选实施方式，不能以此来限定本发明之权利范围，应当指出，对于本技术领域的普通技术人员来说，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种快溶出度的左炔诺孕酮制剂，其特征在于，所述制剂的原料包括：左炔诺孕酮1～2份、一水乳糖32～74份、玉米淀粉20～35份、二氧化硅0.5～4份、羧甲淀粉钠1～6份、硬脂酸镁0.2～2份、十二烷基硫酸钠0.2～2份、羟丙甲纤维素0.2～2份、聚维酮0.2～2份，按重量份计。
2.根据权利要求1所述的左炔诺孕酮制剂，其特征在于，所述制剂的原料包括：左炔诺孕酮1份或2份、一水乳糖44.6份、玉米淀粉33.7份、二氧化硅1.9份、羧甲淀粉钠3.9份、硬脂酸镁0.6份、十二烷基硫酸钠0.3份、羟丙甲纤维素0.5份、聚维酮0.8份，按重量份计。
3.根据权利要求1所述的左炔诺孕酮制剂，其特征在于，所述制剂为片剂、胶囊剂、丸剂、颗粒剂或散剂。
4.一种制备权利要求1～3任一项权利要求所述左炔诺孕酮制剂的方法，其特征在于，包括以下步骤：
S1、取左炔诺孕酮与一水乳糖等量混合均匀后过筛，再将筛下物与一水乳糖等量混合均匀过筛，重复该操作3～6次得到母粉；
S2、将十二烷基硫酸钠、羟丙甲纤维素、聚维酮加入溶剂中并搅散泡发；
S3、向母粉中加入剩余的一水乳糖、玉米淀粉以及部分二氧化硅、羧甲淀粉钠，混合均匀后加入步骤S2所得溶液，混匀干燥制粒后，再加入硬脂酸镁和剩余的二氧化硅、羧甲淀粉钠成型。
5.根据权利要求4所述制备左炔诺孕酮制剂的方法，其特征在于，所述左炔诺孕酮的粒径条件为：99％及以上过80目筛网，所述一水乳糖的粒径条件为：99％及以上过100目筛网。
6.根据权利要求5所述左炔诺孕酮制剂的方法，其特征在于，步骤S1过筛所用筛网的目数为80～120目。
7.根据权利要求6所述左炔诺孕酮制剂的方法，其特征在于，步骤S1过筛所用筛网的目数为80目。
8.根据权利要求4所述制备左炔诺孕酮制剂的方法，其特征在于，所述溶剂为30wt％的乙醇水溶液。
9.根据权利要求4所述制备左炔诺孕酮制剂的方法，其特征在于，所述溶剂的加入量为25～28份。
10.根据权利要求4所述制备左炔诺孕酮制剂的方法，其特征在于，所述搅散泡发的时间为5～10h。
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| WO2008017331A2 (de) * | 2006-08-10 | 2008-02-14 | Bayer Schering Pharma Aktiengesellschaft | Perorale arzneiform mit dienogest und ethinylestradiol zur kontrazeption |
| CN102772377A (zh) * | 2011-05-11 | 2012-11-14 | 北京以岭生物工程技术有限公司 | 一种超微共粉碎左炔诺孕酮片的制备方法 |
| US20150258020A1 (en) * | 2014-03-17 | 2015-09-17 | Anekant Jain | Chewable tablets comprising levonorgestrel |
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| WO2008017331A2 (de) * | 2006-08-10 | 2008-02-14 | Bayer Schering Pharma Aktiengesellschaft | Perorale arzneiform mit dienogest und ethinylestradiol zur kontrazeption |
| CN102772377A (zh) * | 2011-05-11 | 2012-11-14 | 北京以岭生物工程技术有限公司 | 一种超微共粉碎左炔诺孕酮片的制备方法 |
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