CN112957337A - 一种普瑞巴林组合物及其制备方法 - Google Patents
一种普瑞巴林组合物及其制备方法 Download PDFInfo
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- CN112957337A CN112957337A CN202110170974.4A CN202110170974A CN112957337A CN 112957337 A CN112957337 A CN 112957337A CN 202110170974 A CN202110170974 A CN 202110170974A CN 112957337 A CN112957337 A CN 112957337A
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- pregabalin
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Abstract
本发明提供一种普瑞巴林组合物及其制备方法，从而改善生物利用度、食物影响、稳定释放的性能。该组合物其包括粒径为200um‑2500um的普瑞巴林缓释微丸、赋形剂或润滑剂，按质量分数计，所述普瑞巴林缓释微丸的含量为10%‑95%，所述赋形剂的含量为10%‑50%，所述润滑剂的含量为的0.1%‑5%；所述普瑞巴林缓释微丸的活性成分为普瑞巴林或其药学上可接受的盐，所述活性成分的量占所述普瑞巴林缓释微丸质量的约10%‑70%。本发明方法通过溶解、混合、流化床干燥、压片等步骤，制成片剂、胶囊剂、丸剂。本发明制备的普瑞巴林延长释放组合物具有含量均匀、药物释放稳定、生物利用度高并且稳定性良好的特性。
Description
技术领域
本发明属于医药技术领域，具体涉及一种普瑞巴林组合物及其制备方法。
背景技术
普瑞巴林是用于资料神经性疼痛的抗惊厥药物并用于部分性癫痫发作的辅助疗法。普瑞巴林，为辉瑞制药开发，2004年7月，欧盟批准其用于治疗部分癫痫发作，2005年由美国FDA批准上市，用于缓解与治疗神经性疼痛包括糖尿病周围神经病变神经痛（DPN）、带状疱疹后神经痛（PHN）、脊髓损伤相关神经痛、纤维肌痛相关神经痛以及4岁及以上患者癫痫部分发作的治疗。普瑞巴林是首个被美国FDA批准用于糖尿病周围神经病变和带状疱疹后神经痛的药物，也是目前最畅销的镇痛药，其2018年的销售业绩为50亿美元。普瑞巴林有两种制剂，分别为：胶囊（规格：25mg、50mg、75mg、100mg、150mg、225mg、300mg）和口服液（包含20mg/mL普瑞巴林和掩味剂）。在某些适应症中普瑞巴林最大日推荐量为600mg。
普瑞巴林结构简单，是一种新型钙离子通道调节剂【非γ-氨基丁酸(GABA)受体激动剂或拮抗剂】，结构和作用与加巴喷丁相似，具有抗癫痫、镇痛和抗焦虑活性。能阻断电压依赖性钙通道，减少神经递质的释放，临床主要用于治疗外周神经痛以及辅助性治疗局限性部分癫痫发作。化学名称：(S)-(+)-3-(氨甲基)-5-甲基己酸，分子式：C8H17NO2。
由于普瑞巴林半衰期较短（5-6.5h），需要多次给药来维持血药浓度。为了克服这一缺点，本发明提供了一种普瑞巴林缓释胶囊，该胶囊稳定性良好、可以有效解决多次给药的问题，可较长时间维持有效的血药浓度。
目前大多数在开发的普瑞巴林缓控释制剂是基于胃滞留剂型这一方式开发的。
中国专利CN1857244为缓慢释放普瑞巴林组合物，其中包含50mg-1000mg的普瑞巴林活性成分和至少一种释放速度控制材料。该组合物在至少10小时至24小时内释放活性成分。
PCT国际专利WO053003涉及剂型为胃滞留持续释放制剂，该胃滞留持续释放制剂包含普瑞巴林活性成分、聚环氧乙烷和聚乙烯醇-聚乙二醇共聚物，其中通过基质的溶胀和漂浮性来实现滞留于肠胃上部。
微丸是一种剂量分散型，为球形或类球形的口服制剂，添加缓控释材料可制的缓释微丸，可直接装入胶囊中或压成片剂使用。微丸具有增大生物利用度、不受食物影响、释放稳定等优势。故本发明提供一种普瑞巴林缓释微丸及其药物组合的制备方法。
发明内容
为了克服现有技术中缺少非胃滞留剂型的问题，从而提供一种普瑞巴林组合物及其制备方法，从而改善生物利用度、食物影响、稳定释放的性能。
为解决上述技术问题，本发明提供如下技术方案：一种普瑞巴林延长释放组合物，其包括，粒径为200um-2500um的普瑞巴林缓释微丸、赋形剂或润滑剂，按质量分数计，所述普瑞巴林缓释微丸的含量为10%-95%，所述赋形剂的含量为10%-50%，所述润滑剂的含量为的0.1%-5%；所述普瑞巴林缓释微丸的活性成分为普瑞巴林或其药学上可接受的盐，所述活性成分的量占所述普瑞巴林缓释微丸质量的约10%-70%。
优选的，所述普瑞巴林缓释微丸含有基底微丸、粘合剂、缓释材料、抗粘剂，所述基底微丸占所述普瑞巴林缓释微丸质量的10%-70%，所述粘合剂占所述普瑞巴林缓释微丸质量的1%-20%，所述缓释材料占所述普瑞巴林缓释微丸质量的1%-20%，所述抗粘剂占所述普瑞巴林缓释微丸质量的1%-10%。
优选的，所述赋形剂包括交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠、微晶纤维素、淀粉、预胶化淀粉、蔗糖、糊精、甘露醇、硫酸钙、磷酸钙、磷酸氢钙中的一种或几种，所述润滑剂包括硬脂酸镁、氢化植物油、硬脂酸、硬脂富马酸钠中的一种或几种。
优选的，所述缓释材料包括聚甲基丙烯酸酯、乙基纤维素、聚乙烯、无毒聚氯乙烯、乙烯-醋酸乙烯共聚物中的一种或一种以上的组合物；所述粘合剂包括羟丙纤维素、羟丙甲纤维素、泊洛沙姆、聚维酮、共聚维酮、聚乙二醇中的一种或几种；所述抗粘剂为滑石粉。
优选的，所述普瑞巴林缓释微丸粒径为500um-1200um，所述活性成分的量占所述普瑞巴林缓释微丸质量的约30%-70%。
作为本发明的另一方面本发明提供一种普瑞巴林延长释放组合物的制备方法，其包含以下步骤，称取处方量普瑞巴林、缓释材料、抗粘剂、粘合剂，先将缓释材料完全溶解于溶剂中，然后加入粘合剂，搅拌至完全溶解，再加入普瑞巴林和抗粘剂，搅拌至分散均匀，维持搅拌，备用；称取处方量的基底微丸，置于流化床中，以底喷上药的方式加入药物混悬溶液，进行流化床层积上药，得到普瑞巴林缓释微丸。
优选的，所述普瑞巴林缓释微丸可与药用辅料制成片剂、胶囊剂、丸剂。
本发明制备的普瑞巴林延长释放组合物具有含量均匀、药物释放稳定、生物利用度高并且稳定性良好的特性。
附图说明
图1为普瑞巴林延长释放制剂在0.1N盐酸介质中，采用篮法100rpm、溶出介质900mL检测溶出曲线，。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合说明书附图对本发明的具体实施方式做详细的说明。
实施例1
制备了含有普瑞巴林缓释微丸的胶囊剂。处方如下：
缓释微丸的制备方法如下:
（1）称取处方量普瑞巴林、乙基纤维素、滑石粉、羟丙纤维素，先将乙基纤维素完全溶解于80%乙醇溶剂中，然后加入羟丙纤维素，300rpm搅拌至完全溶解，再加入普瑞巴林和滑石粉，搅拌至分散均匀，维持搅拌，得到药物混悬溶液，备用；
（2）称取处方量的粒径为300um-500um的蔗糖微丸，置于流化床中，以底喷上药的方式加入步骤（1）中的药物混悬溶液，设置进风频率为25Hz~35Hz，物化压力1.3bar~1.7bar，蠕动泵转速12rpm~25rpm，控制物料温度27℃~35℃，进行流化床层积上药，控制物料温度27℃~35℃，制得所述的普瑞巴林缓释微丸。所得微丸颗粒性质检测结果如下：
药物组合物的制备:
将缓释微丸直接填充至00#明胶胶囊中，即得普瑞巴林缓释胶囊。
实施例2
制备了含普瑞巴林缓释微丸的片剂。
处方：
缓释微丸的制备:
称取处方量普瑞巴林、乙基纤维素、滑石粉、羟丙纤维素，先将乙基纤维素完全溶解于80%乙醇溶剂中，然后加入羟丙纤维素，300rpm搅拌至完全溶解，再加入普瑞巴林和滑石粉，搅拌至分散均匀，维持搅拌，备用；
称取处方量的粒径为300um-500um的蔗糖微丸，置于流化床中，以底喷上药的方式加入药物混悬溶液，设置进风频率为25Hz~35Hz，物化压力1.3bar~1.7bar，蠕动泵转速12rpm~25rpm，控制物料温度27℃~35℃，进行流化床层积上药，制得所述的普瑞巴林缓释微丸。所得微丸颗粒性质检测结果如下：
药物组合物的制备:
将缓释微丸与微晶纤维素、硬脂酸镁混合均匀，采用ZP-14压片机，按直径16mm圆形冲，进行压片，目标硬度200N，即得普瑞巴林缓释片。
实施例3
制备了含有普瑞巴林缓释微丸的胶囊剂。
处方：
制备：
缓释微丸的制备:
称取处方量普瑞巴林、乙基纤维素、滑石粉、羟丙纤维素，先将乙基纤维素完全溶解于80%乙醇溶剂中，然后加入羟丙纤维素，300rpm搅拌至完全溶解，再加入普瑞巴林和滑石粉，搅拌至分散均匀，维持搅拌，备用；
称取处方量的粒径为300um-500um的蔗糖微丸，置于流化床中，以底喷上药的方式加入药物混悬溶液，设置进风频率为25Hz~35Hz，物化压力2.0bar，蠕动泵转速12rpm~25rpm，控制物料温度27℃~35℃，进行流化床层积上药，得到所述的普瑞巴林缓释微丸。所得微丸颗粒性质检测结果如下：
药物组合物的制备:
将缓释微丸与硬脂酸镁混合，填充至00#明胶胶囊中，即得普瑞巴林缓释胶囊。
实施例4
制备了含普瑞巴林缓释微丸的片剂。
处方：
缓释微丸的制备:
称取处方量普瑞巴林、乙基纤维素、滑石粉、羟丙纤维素，先将乙基纤维素完全溶解于80%乙醇溶剂中，然后加入羟丙纤维素，300rpm搅拌至完全溶解，再加入普瑞巴林和滑石粉，搅拌至分散均匀，维持搅拌，备用；
称取处方量的粒径为300um-500um的蔗糖微丸，置于流化床中，以底喷上药的方式加入药物混悬溶液，设置进风频率为30Hz~40Hz，物化压力2.0bar，蠕动泵转速12rpm~25rpm，控制物料温度27℃~35℃，进行流化床层积上药，得到所述的普瑞巴林缓释微丸。所得微丸颗粒性质检测结果如下：
药物组合物的制备:
将缓释微丸与微晶纤维素、硬脂酸镁混合均匀，采用ZP-14压片机，按直径18mm圆形冲，进行压片，目标硬度250N，即得普瑞巴林缓释片。
本发明中为一种普瑞巴林延长释放组合物，其中普瑞巴林缓释微丸和药学上可接受的赋形剂、润滑剂等组成。本发明所述的普瑞巴林组合物的普瑞巴林缓释微丸可以通过对基底微丸涂敷普瑞巴林与缓释材料和/或粘合剂和抗粘剂的共溶液制得，该基底微丸为任何药物可接受填充剂和粘合剂进行制备。将得到的缓释微丸与药物上可接受的赋形剂、润滑剂混合产生一种适合用于包装或压片或填充胶囊的组合物。
本发明提供了一种普瑞巴林或其盐的延长释放的药物组合物，通过将普瑞巴林活性成分与缓释材料共同涂敷于载体微丸材料上，使其缓慢而稳定的释放。同时含有该缓释微丸的药物组合物具有溶出稳定，稳定性好等特点，符合临床用药的要求，并提高了患者用药的安全性。
本发明的另一目的在于提供一种普瑞巴林延长释放药物组合物，所述药物组合物由本发明所述的普瑞巴林缓释微丸与药用辅料组成。所述普瑞巴林缓释微丸通过流化床法、离心造粒法进行制备，视制剂的需要，所述药用辅料可以包含崩解剂、粘合剂、填充剂、润滑剂等中的一种或两种以上的混合物。所述崩解剂选自交联羧甲基纤维素钠、干淀粉、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、淀粉、预胶化淀粉等中的一种或多种的混合物；所用崩解剂的量以本领域公知的能实现崩解效果的量为准，优选的，所述药物组合物中崩解剂的含量为0.5%～5%。所述填充剂可以视制剂处方的需要选择添加或不添加，具体的，所述填充剂选自蔗糖、甘露醇、糊精、微晶纤维素、木糖醇、淀粉、预胶化淀粉、乳糖、硫酸钙、磷酸钙、磷酸氢钙等中的一种或多种的混合物，所用填充剂的量以本领域公知的能实现填充效果的量为准，优选的，所述药物组合物中填充剂的质量比为10%～70%。粘合剂粘可使用羟丙纤维、聚维酮、共聚聚维酮、羟丙甲纤维素等，所述的羟丙纤维素规格以平均分子量分类有EF、LF、JF、GF、MF等。所述聚维酮为1-乙烯基-2-吡咯烷酮均聚物，其规格以平均分子量分类有PVP k12、PVP k15、PVP k17、PVP k25、PVP k30、PVP k29/32、PVP k60、PVP k120等，优选PVP k29/32。
应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。
Claims (7)
1.一种普瑞巴林延长释放组合物，其特征在于：包括粒径为200um-2500um的普瑞巴林缓释微丸、赋形剂或润滑剂，按质量分数计，所述普瑞巴林缓释微丸的含量为10%-95%，所述赋形剂的含量为10%-50%，所述润滑剂的含量为的0.1%-5%；
所述普瑞巴林缓释微丸的活性成分为普瑞巴林或其药学上可接受的盐，所述活性成分的量占所述普瑞巴林缓释微丸质量的约10%-70%。
2.如权利要求1所述的普瑞巴林延长释放组合物，其特征在于：所述普瑞巴林缓释微丸含有基底微丸、粘合剂、缓释材料、抗粘剂，所述基底微丸占所述普瑞巴林缓释微丸质量的10%-70%，所述粘合剂占所述普瑞巴林缓释微丸质量的1%-20%，所述缓释材料占所述普瑞巴林缓释微丸质量的1%-20%，所述抗粘剂占所述普瑞巴林缓释微丸质量的1%-10%。
3.如权利要求1所述的普瑞巴林延长释放组合物，其特征在于：所述赋形剂包括交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠、微晶纤维素、淀粉、预胶化淀粉、蔗糖、糊精、甘露醇、硫酸钙、磷酸钙、磷酸氢钙中的一种或几种，所述润滑剂包括硬脂酸镁、氢化植物油、硬脂酸、硬脂富马酸钠中的一种或几种。
4.如权利要求2所述的普瑞巴林延长释放组合物，其特征在于：所述缓释材料包括聚甲基丙烯酸酯、乙基纤维素、聚乙烯、无毒聚氯乙烯、乙烯-醋酸乙烯共聚物中的一种或一种以上的组合物；
所述粘合剂包括羟丙纤维素、羟丙甲纤维素、泊洛沙姆、聚维酮、共聚维酮、聚乙二醇中的一种或几种；
所述抗粘剂为滑石粉。
5.如权利要求1所述的普瑞巴林延长释放组合物，其特征在于：所述普瑞巴林缓释微丸粒径为500um-1200um，所述活性成分的量占所述普瑞巴林缓释微丸质量的约30%-70%。
6.一种普瑞巴林延长释放组合物的制备方法，其特征在于：包含以下步骤，
称取处方量普瑞巴林、缓释材料、抗粘剂、粘合剂，先将缓释材料完全溶解于溶剂中，然后加入粘合剂，搅拌至完全溶解，再加入普瑞巴林和抗粘剂，搅拌至分散均匀，维持搅拌，备用；
称取处方量的基底微丸，置于流化床中，以底喷上药的方式加入药物混悬溶液，进行流化床层积上药，得到普瑞巴林缓释微丸。
7.如权利要求6所述的普瑞巴林延长释放组合物的制备方法，其特征在于：所述普瑞巴林缓释微丸可与药用辅料制成片剂、胶囊剂、丸剂。
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