CN118236356B - 一种特立氟胺口溶膜及其制备方法、应用和药物组合物 - Google Patents
一种特立氟胺口溶膜及其制备方法、应用和药物组合物 Download PDFInfo
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- CN118236356B CN118236356B CN202410669435.9A CN202410669435A CN118236356B CN 118236356 B CN118236356 B CN 118236356B CN 202410669435 A CN202410669435 A CN 202410669435A CN 118236356 B CN118236356 B CN 118236356B
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- teriflunomide
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- 229960000331 teriflunomide Drugs 0.000 title claims abstract description 72
- 229940100688 oral solution Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
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Abstract
本发明提供了一种特立氟胺口溶膜及其制备方法、应用和药物组合物，属于药物制剂领域。所述的特立氟胺口溶膜按照重量份数计包括特立氟胺10‑20份、成膜剂55‑130份、崩解剂15‑40份、增塑剂15‑35份和调味剂4‑15份；所述的特立氟胺口溶膜的pH为6.8‑10.0。本发明提供的特立氟胺口溶膜的膜厚度、抗拉强度、伸长率、干燥失重、溶化时间和适口性均符合上市口溶膜标准，有关物质满足已上市口服片剂质量标准要求，并且其稳定性符合ICH、药典以及上市制剂要求。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种特立氟胺口溶膜及其制备方法、应用和药物组合物。
背景技术
特立氟胺(Teriflunomide)，化学名为(2Z)-氰基-3-羟基-N-[4-(三氟甲基)苯基]-2-丁烯酰胺。其分子式为C12H9F3N2O2，分子量为270.21。特立氟胺是一种具有抗炎作用的免疫调节剂，可抑制二氢乳清酸脱氢酶，该酶是一种参与嘧啶从头合成的线粒体酶。
多发性硬化（MS）是一种免疫介导的中枢神经系统慢性炎性脱髓鞘性疾病，通过炎症和组织损伤破坏大脑、视神经和脊髓的正常功能。MS的临床表现多样，累及部位广泛，临床表现反复多变，确诊难度大。特立氟胺可有效的治疗多发性硬化，治疗疗效较好，其总体耐受性良好，未发现新的安全性问题。
中国专利CN106880601A中公开了一种含有特立氟胺的口腔崩解片及其制备方法。该口腔崩解片含有特立氟胺、亲水性填充剂、水溶性粘合剂、崩解剂、润滑剂及矫味剂等。将特立氟胺与亲水性填充剂中的一种或多种进行共微粉化，加入水溶性粘合剂的水溶液制湿软材，制粒。该剂型为崩解片剂，添加了水溶性粘合剂，制作工艺复杂，崩解及吸收速度较口溶膜慢。
多发性硬化症患者在临床表现上主要有视力下降、复视、肢体感觉障碍、肢体运动障碍、共济失调、膀胱或直肠功能障碍等。在患者服用特立氟胺片剂时，存在吞咽困难、需饮水服药致加剧膀胱控制困难以及患者主观抗拒服药，导致治疗时患者用药依从性不佳影响治疗效果等问题。
口溶膜剂，是基于透皮贴剂技术开发的一种新型口服给药系统，在不喝水或咀嚼的情况下放入口中，可在1分钟内分解或溶解。作为膜剂的一种，可替代片剂、糖浆或栓剂，用于治疗呕吐和恶心，因为可以避免吞咽大量液体，尤其适合于儿科人群和老年人群。将口溶膜放置在患者的舌头或其他口腔粘膜组织上。由于口溶膜中含有亲水性聚合物和其他辅料的存在，薄膜会立即被唾液润湿，迅速水合并附着在使用部位，快速溶解以释放药物。其快速分解或溶解或分解以释放药物，一部分用于粘膜吸收，一部分经修饰后快速溶解在胃肠道吸收，开发一款易于吞咽，不用或少用水服药的特立氟胺口溶膜能够帮助提高患者用药依从性，有利于患者疾病的治疗与控制。
然而，特立氟胺不稳定，在有水存在的情况下，高温、高湿和光照条件下易降解产生杂质，尤以杂质B、杂质A和部分未知杂质易于产生和难以控制，对特立氟胺口溶膜剂型的开发带来了极大的挑战。
因此，开发一种稳定性较高，符合制剂质量标准的特立氟胺口溶膜是目前亟需解决的技术问题。
发明内容
为了解决上述问题，本发明提供了一种稳定的特立氟胺口溶膜及其制备方法，特立氟胺口溶膜的膜厚度、抗拉强度、伸长率、干燥失重、溶化时间和适口性均符合上市口溶膜标准，有关物质满足已上市口服片剂质量标准要求，且稳定性符合ICH、药典以及上市制剂要求。
一方面，本发明提供了一种特立氟胺口溶膜，所述的特立氟胺口溶膜按照重量份数计包括特立氟胺10-20份、成膜剂55-130份、崩解剂15-40份、增塑剂15-35份和调味剂4-15份；所述的特立氟胺口溶膜的pH为6.8-10.0。
优选地，所述的特立氟胺口溶膜按照重量份数计包括特立氟胺10-14份、成膜剂125-130份、崩解剂35-40份、增塑剂30-35份和调味剂4-5份；所述的特立氟胺口溶膜的pH为6.8-8.5。
进一步地，所述的特立氟胺口溶膜的pH为7.0-7.8。
具体地，所述的成膜剂选自羟丙甲纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚氧乙烯、乙基纤维素水分散体中的一种或多种。
进一步地，所述的乙基纤维素水分散体的组成为：乙基纤维素（26.2%）、十二烷基硫酸钠（1.2%）、十六醇（2.7%），其余为水。
进一步具体地，所述的乙基纤维素水分散体的型号为Aquacoat ECD-30。
具体地，所述的崩解剂选自甘露醇、蔗糖、乳糖、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙纤维素中的一种或多种。
具体地，所述的增塑剂选自甘油、聚乙二醇、丙二醇、丙三醇、山梨醇、木糖醇中的一种或多种。
具体地，所述的调味剂包括甜味剂和芳香剂。
进一步地，所述的甜味剂选自三氯蔗糖、蔗糖、木糖醇、结晶果糖、麦芽糖、糖精、甜蜜素、甜菊糖苷、甘草酸二钠、甘草酸三钾、甘草酸三钠中的一种或多种。
进一步地，所述的芳香剂选自薄荷油、薄荷脑、桉叶油、樟脑油、丁香油、桂皮油中的一种或多种。
再进一步地，所述的芳香剂选自薄荷油、薄荷脑中的一种或多种。
具体地，所述的特立氟胺口溶膜的pH使用pH调节剂进行调节。
进一步地，所述的pH调节剂选自所述的pH调节剂选自硫酸二氢钠、硫酸氢二钠、磷酸氢钠、磷酸氢二钠、磷酸二氢钠、磷酸氢钾、磷酸氢二钾、磷酸二氢钾、氢氧化钠、氢氧化钾、柠檬酸、苹果酸、琥珀酸、酒石酸、盐酸、醋酸中的一种或多种。
再进一步地，所述的pH调节剂选自硫酸二氢钠、硫酸氢二钠、氢氧化钠中的一种或多种。
具体地，所述的特立氟胺口溶膜还包括溶剂。
进一步地，所述的溶剂包括水和乙醇。
具体地，所述的乙醇为药用无水乙醇。
又一方面，本发明提供了特立氟胺口溶膜的制备方法，包括以下步骤：
（1）将聚乙烯醇溶解，得到聚乙烯醇溶液；
（2）向聚乙烯醇溶液中加入特立氟胺、pH调节剂，混匀，再加入成膜剂、崩解剂、增塑剂、甜味剂，混匀，得胶液；
（3）将芳香剂溶于乙醇后加入至胶液中，涂布，干燥，得特立氟胺口溶膜；
步骤（2）中所述的胶液的pH为6.8-10.0。
进一步地，步骤（2）中所述的胶液的pH为6.8-8.5。
再进一步地，步骤（2）中所述的胶液的pH为7.0-7.8。
又一方面，本发明提供了上述的特立氟胺口溶膜或上述的制备方法制备得到的特立氟胺口溶膜在制备药物组合物中的应用。
具体地，所述的药物组合物用于治疗多发性硬化症。
又一方面，本发明提供了一种药物组合物，所述的药物组合物中包含上述的特立氟胺口溶膜或上述的制备方法制备得到的特立氟胺口溶膜。
具体地，所述的药物组合物中还可以包括药学上可接受的载体。
进一步地，所述的药学上可接受的载体选自赋形剂、缓冲剂、乳化剂、稳定剂、稀释剂、粘合剂、防腐剂、润滑剂中的一种或多种。
具体地，所述赋形剂选自微晶纤维素、乳糖、预胶化淀粉、环糊精、羧甲基纤维素、甘露醇中的至少一种。
具体地，所述缓冲剂选自磷酸二氢钠、碳酸氢钠、碳酸氢铵、醋酸钠、枸橼酸盐、组氨酸、琥珀酸盐中的至少一种。
具体地，所述乳化剂选自硬脂酸镁、硬脂酸锌、硬脂酸钙、硬脂酸甘油酯、山梨坦异硬脂酸酯、山梨坦油酸酯、甘油油酸酯、聚甘油-3聚蓖麻醇酸酯中的至少一种。
具体地，所述稳定剂选自金合欢胶、琼脂、藻酸、纤维素醚、羧甲基甲壳酯中的至少一种。
具体地，所述稀释剂选自赤藓糖醇、甘露醇、山梨糖醇、木糖醇、乳糖、蔗糖、玉米淀粉、马铃薯淀粉、磷酸钙、柠檬酸钙、结晶纤维素中的至少一种。
具体地，所述粘合剂选自乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮中的至少一种。
具体地，所述防腐剂选自羟苯甲酸甲酯、对羟苯甲酸丙酯、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、三氯叔丁醇、硫柳汞、氧氰化汞、苯氧乙醇、氯己定、苯甲酸、苯甲酸钠、氯甲酚、苯扎溴铵、苯扎氯铵、羟苯乙酯中的至少一种。
具体地，所述润滑剂选自硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆中的至少一种。
具体地，所述药物组合物的剂型为滴剂、合剂、酊剂、注射剂、片剂、粉剂、口服液、胶囊剂、颗粒剂、软膏剂、混悬剂、散剂、乳剂、溶液剂、滴丸剂、丸剂、口含片、冻干粉针剂、凝胶、栓剂或气雾剂。
本发明的有益效果：
本发明提供了一种特立氟胺口溶膜，其膜厚度、抗拉（张）强度、伸长率、干燥失重、溶化时间和适口性均符合上市口溶膜标准，有关物质满足已上市口服片剂质量标准要求。本发明在特立氟胺口溶膜的制备过程通过使用pH调节剂控制在6.8-10.0之间，尤其在当pH范围在6.8-8.5之间，特别地当pH在7.0-7.8之间，成品有关物质情况及其稳定性符合ICH、药典以及上市制剂要求。
具体实施方式
下面结合具体实施例，对本发明作进一步详细的阐述，下述实施例不用于限制本发明，仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明，实施例中未注明具体条件的实验方法，通常按照常规条件，下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实验材料的购买厂家及货号：
特立氟胺购自合肥恩瑞特公司，批号为AQ26220301；
乙基纤维素水分散体的型号为Aquacoat ECD-30，组成为：乙基纤维素（26.2%）、十二烷基硫酸钠（1.2%）、十六醇（2.7%），水，批号：ZNR580962。
羟丙甲纤维素购自上海卡陆康包衣技术有限公司，批号为D011KBTL01；
聚乙烯醇购自江西阿尔法公司，批号为 20230401；
薄荷脑购自安徽华馨公司，批号为HM230111001；
聚氧乙烯购自上海卡陆康包衣技术有限公司，货号为20230801；
三氯蔗糖购自盐城捷康公司，批号为Y22080601；
甜菊糖苷购自曲阜圣仁公司，批号为23092010；
甘露醇购自九典宏阳公司，批号为TF84221003；
丙二醇购自九典宏阳公司，批号为TF31230901；
药用无水乙醇购自安徽安特公司，批号为20230428；
氢氧化钠购自南京化学试剂股份有限公司，批号为P2501569。
本发明实施例和对比例特立氟胺口溶膜的处方组成如下：
表1.
表2.
实施例和对比例的特立氟胺口溶膜的制备包括以下步骤：
试验例1 物理特性试验
对实施例和对比例制备的特立氟胺口溶膜进行物理特性的检测：
溶化时间：使样品置于温度为(37 ± 0.5)℃的装有 20 mL 纯化水的培养皿中，记录样品完全溶解的时间即为崩解时间。
伸长率：伸长率是指膜受外力拉伸，断裂时增加的长度与原始长度的比值。使用智能电子拉力试验机进行测定，计算公式：伸长率= 长度增加量/原长×100。
抗拉强度：抗拉强度也叫强度极限，是指拉断口腔膜剂时所用的最大的力。使用智能电子拉力试验机，方法同伸长率。计算公式为: 抗拉强度= 外加应力/横截面积。
检测结果如表3。
表3.
| 考察项目 | 目标 | 对比例1 | 对比例2 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 | 实施例8 |
| 溶化时间/s | ≤60 | 48 | 42 | 35 | 40 | 45 | 38 | 44 | 39 | 37 | 51 |
| 抗拉强度/ Mpa | >1 | 3.7 | 4.5 | 4.3 | 3.5 | 3.9 | 4.1 | 4.0 | 3.5 | 4.8 | 4.3 |
| 伸长率/% | >2 | 7.4 | 8.2 | 7.2 | 7.7 | 7.3 | 7.1 | 8.1 | 7.3 | 5.6 | 7.1 |
从表3中可以看出，实施例和对比例处方下所得特立氟胺口溶膜均具备良好的机械性能，在物理特性上满足膜剂的一般要求。
试验例2 稳定性检测
为充分研究各实施例和对比例处方对产品稳定性尤其是对具有较高风险的有关物质检测项的影响，将各实施例与对比例下所得样品置于药品加速试验条件（温度40℃±2℃、相对湿度75%±5%）和长期试验条件（25℃±2℃、相对湿度60%±5%）的稳定性试验箱内放置，并于加速1个月，加速6个月和长期12个月时取样检测有关物质。
产品有关物质检测方法如下：
按照高效液相色谱法（中国药典2020年版四部通则0512）测定。
溶剂 pH5.5醋酸铵溶液（取醋酸铵3.85g，加水1000ml溶解，用冰醋酸调节pH值至5.5）-乙腈（20:80）。
供试品溶液：取本品5片，置50ml量瓶中（7mg规格）或100ml量瓶中（14mg规格），加20%量瓶体积的pH5.5醋酸铵溶液，振摇使口溶膜溶解（必要时可超声），用乙腈稀释至刻度，摇匀，离心，精密量取上清液适量，用稀释剂定量稀释制成每1ml中约含特立氟胺0.14mg的溶液。
系统适用性溶液：取特立氟胺对照品、杂质A对照品、杂质B对照品适量，精密称定，加乙腈溶解并用溶剂定量稀释制成每1ml中约含特立氟胺0.14mg或7mg，杂质A 0.01407μg，杂质B 0.422.1μg的溶液。
对照品溶液：取特立氟胺对照品适量，精密称定，加乙腈溶解并用溶剂定量稀释制成每1ml中约含0.147μg的溶液。
灵敏度溶液：取特立氟胺对照品适量，精密称定，加乙腈溶解并用溶剂定量稀释制成每1ml中约含0.0735μg的溶液。
色谱条件：用十八烷基硅烷键合硅胶为填充剂（Welch Ultimate XB-C18SupelcoAscentis Express，4.6mm×150mm，32.7μm 或效能相当的色谱柱），以pH5.5醋酸铵溶液-乙腈（90:10）为流动相A，以pH5.5醋酸铵溶液-乙腈（10:90）为流动相B，按下表进行线性梯度洗脱，检测波长为249nm；流速为每分钟1.0ml；柱温为40℃；进样体积520μl。
表4.
| 时间（分钟） | 流动相A（%） | 流动相B（%） |
| 0 | 76 | 24 |
| 17 | 23 | 77 |
| 18 | 76 | 24 |
| 25 | 76 | 24 |
系统适用性要求：系统适用性溶液色谱图中，特立氟胺、杂质B与杂质A依次出峰，杂质A峰与杂质B峰之间的分离度应不小于1.5，杂质A峰的信噪比应不小于10；灵敏度溶液主成分峰高的信噪比应大于10。
测定法：精密量取供试品溶液与对照品溶液，分别注入液相色谱仪，记录色谱图。
限度：供试品溶液中如有杂质峰，按加校正因子的主成分外标法计算，各杂质的含量应符合下表规定；除杂质A外，小于灵敏度溶液主峰面积的色谱峰忽略不计（0.05%）。
表5.
| 杂质名称 | 校正因子 | 限度（%） |
| 杂质A | 1.2 | 0.01 |
| 杂质B | 1.2 | 0.30 |
| 其他单个杂质 | 1.0 | 0.10 |
| 总杂质 | —— | 0.40 |
检测结果如下表6所示。
表6.
从上表6中可以看出，胶液pH低于6.0的对比例1和2，在0天时有关物质即超出拟定标准，当pH大于等于6.8的情况下（实施例1-8）稳定性研究结果表明，所得口溶膜在0天、加速6M和长期12M时稳定性均满足要求。
为证实胶液pH是本品口溶膜稳定性期间有关物质变化的关键因素，使用了其它处方对产品稳定性进行了考察。结果表明胶液pH直接影响产品有关物质。在既定的pH范围：6.8-10.0范围内，产品有关物质能够得以控制。
表7.
特立氟胺口溶膜的制备包括以下步骤：
（1）将蔗糖置于适当容器中，加入乙醇/水溶液（乙醇：水=1：2）中。搅拌待完全溶解后加入特立氟胺，搅拌均匀后，加入3/5配方量聚氧乙烯，搅拌均匀；
（2）取纯化水加热至85-95℃后，边搅拌边加入羟丙甲纤维素，搅拌均匀后冷却至室温，之后加入聚乙烯吡咯烷酮（PVP）、2/5配方量聚氧乙烯和聚乙二醇，搅拌至完全溶解；
（3）将（2）中胶液边搅拌边加入（1）中，之后加入三氯蔗糖和薄荷油并加入pH调节剂高速剪切2分钟，反复5次；
（4）静置真空消泡，使用口溶膜涂布干燥机进行涂布和干燥，裁切，包装即得。
稳定性的检测结果如下表所示。
表8.
Claims (6)
1.一种特立氟胺口溶膜，其特征在于，所述的特立氟胺口溶膜按照重量份数计包括特立氟胺10-20份、成膜剂55-130份、崩解剂15-40份、增塑剂15-35份和调味剂4-15份；所述特立氟胺口溶膜的制备过程通过使用pH调节剂控制pH在6.8-10.0之间；
所述的成膜剂选自羟丙甲纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚氧乙烯、乙基纤维素水分散体中的一种或多种；
所述的崩解剂选自甘露醇、蔗糖、乳糖、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙纤维素中的一种或多种；
所述的增塑剂选自甘油、聚乙二醇、丙二醇、山梨醇、木糖醇中的一种或多种。
2.根据权利要求1所述的特立氟胺口溶膜，其特征在于，所述的特立氟胺口溶膜按照重量份数计包括特立氟胺10-14份、成膜剂125-130份、崩解剂35-40份、增塑剂30-35份和调味剂4-5份；所述特立氟胺口溶膜的制备过程通过使用pH调节剂控制pH在6.8-8.5之间。
3.根据权利要求1-2任一项所述的特立氟胺口溶膜，其特征在于，所述的调味剂包括甜味剂和芳香剂；
所述的甜味剂选自三氯蔗糖、蔗糖、木糖醇、结晶果糖、麦芽糖、糖精、甜蜜素、甜菊糖苷、甘草酸二钠、甘草酸三钾、甘草酸三钠中的一种或多种；
所述的芳香剂选自薄荷油、薄荷脑、桉叶油、樟脑油、丁香油、桂皮油中的一种或多种。
4.根据权利要求1所述的特立氟胺口溶膜，其特征在于，所述的特立氟胺口溶膜的pH使用pH调节剂进行调节；所述的pH调节剂选自磷酸氢二钠、磷酸二氢钠、磷酸氢二钾、磷酸二氢钾、氢氧化钠、氢氧化钾、柠檬酸、苹果酸、琥珀酸、酒石酸、盐酸、醋酸中的一种或多种。
5.权利要求1-4任一项所述的特立氟胺口溶膜在制备治疗多发性硬化症的药物组合物中的应用。
6.一种药物组合物，其特征在于，所述的药物组合物中包含权利要求1-4任一项所述的特立氟胺口溶膜。
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