CN112843062A - 一种含盐酸曲普利啶口服溶液及其制备方法 - Google Patents
一种含盐酸曲普利啶口服溶液及其制备方法 Download PDFInfo
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- CN112843062A CN112843062A CN201911187985.2A CN201911187985A CN112843062A CN 112843062 A CN112843062 A CN 112843062A CN 201911187985 A CN201911187985 A CN 201911187985A CN 112843062 A CN112843062 A CN 112843062A
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- oral solution
- essence
- acid
- hydrochloride
- triprolidine hydrochloride
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Abstract
本发明属于药物制剂领域，具体涉及一种含有曲普利啶的复方口服溶液制剂。本发明复方盐酸曲普利啶口服溶液剂使用药学上可接受的辅料，准确分剂量，提高用药安全性，加入芳香剂和甜味剂，口感较好，使用刻度滴管准确分剂量，尤其适用于儿童。本发明产品质量可控和稳定性高，工艺简单，易于吸收，疗效确切，更好的满足临床需要。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种含有曲普利啶的复方口服溶液制剂。
背景技术
过敏性疾病一般以速发型过敏反应又称Ⅰ型变态反应为主，主要引起如过敏性鼻炎、哮喘、结膜炎、湿疹、食物过敏、药物过敏和严重过敏反应等。在过去几十年中，过敏性疾病发病率显著上升，已经严重影响到儿童和成人的生活质量，甚至危及生命，已经成为全球关注的公众卫生问题。
免疫球蛋白E(IgE)是介导Ⅰ型变态反应的抗体。在人体内存在两种IgE受体：高亲和力受体FcεRI和低亲和力受体FcεRII，前者表达于肥大细胞，嗜碱性粒细胞，后者表达于B细胞、单核巨噬细胞，嗜酸性粒细胞、树突细胞等。IgE的Fc段中特殊部位与肥大细胞表面的FcεRI结合，使机体处于对该过敏原的致敏状态。当再次接触过敏原后，过敏原与两个分子的IgE结合，触发细胞膜的一系列生化反应。如可导致肥大细胞脱颗粒，而导致肥大细胞脱颗粒的化学物质中最主要的是组胺。因此，组胺、肥大细胞和IgE抗体对过敏性疾病的治疗是密切相关的。抗组胺药即H1受体拮抗剂通过与H1受体竞争性结合来抑制组胺与H1受体作用，从而抑制组胺的生物学效应来抗过敏。
盐酸曲普利啶(Triprolidine hydrochloride)，分子式：C19H23ClN2；分子量：314.85；化学结构式如下：
盐酸曲普利啶属特异性组胺H1受体阻断剂，能与组胺竞争效应细胞上的组胺H1受体，使组胺不能与受体结合，从而抑制其作用，故可完全对抗组胺收缩胃、肠、气管、支气管平滑肌的作用。对组胺引起的皮肤反应的抑制作用，该药明显高于新赛克利嗪(止吐嗪，cyclizine)。在缓解组胺引起的豚鼠回肠痉挛方面，盐酸曲普利啶的活性高于甲氧苄二胺(mpeyramine)，并且高于其众多的结构类似物；对过敏性休克，具有比甲氧苄二胺更强的保护作用，为第一代抗组胺药，用于治疗过敏、感冒、鼻炎等病症。
盐酸曲普利啶活性强副作用小，口服吸收迅速，临床上得到广泛应用。盐酸曲普利啶在市场上产品的形式主要为口服溶液剂、片剂、胶囊。片剂、胶囊因尺寸、形状差异，存在吞咽困难，容易粘附于食道，引起恶心、窒息、嗳气等不良反应。昏迷病人、老人、儿童对片剂、胶囊顺应性较差。口服溶液剂在人体内无需崩解溶出，吸收速度更快，可以准确分剂量，尤其适用于婴幼儿。目前，美国有含盐酸曲普利啶口服溶液剂上市销售，但产品中同时含有甘草酸单铵盐，甘草酸单铵盐对气管炎、支气管炎、咳嗽、哮喘等呼吸系统疾病有显著疗效，当其治疗过敏性疾病时对呼吸系统产生作用，可能增加药物副作用，引起不良反应。
氢溴酸右美沙芬是中枢性镇咳药，可抑制延脑咳嗽中枢而产生镇咳作用。其镇咳作用与可待因相等或稍强，治疗剂量不抑制呼吸，长期服用无成瘾性和耐受性。
去氧肾上腺素可通过收缩血管、升高血压使迷走神经反射地兴奋而心率减慢，临床上通常用于阵发性室上性心动过速。还有一些情况下需要去氧肾上腺素在体内持续发挥作用，但由于活性去氧肾上腺素类物质在体内的血浆半衰期短，所以去氧肾上腺素通常每隔一段时间给药一次。给患者带来了不便，也降低了去氧肾上腺素在受试者体内的持续性。
考虑到不同生理阶段人群的承受能力和服药依从性，同时国内无盐酸曲普利啶口服溶液剂上市销售，我们发明了一种含有盐酸曲普利啶的复方制剂，且稳定有效、口感较好，用于治疗上呼吸道感染、支气管炎引起的咳嗽、咳痰的口服溶液剂。
发明内容
本发明的目的在于：提供一种稳定有效的含有盐酸曲普利啶口服溶液剂及其制备方法。本发明复方盐酸曲普利啶口服溶液剂使用药学上可接受的辅料，准确分剂量，提高用药安全性，加入芳香剂和甜味剂，口感较好，使用刻度滴管准确分剂量，尤其适用于儿童。本发明产品质量可控和稳定性高，工艺简单，易于吸收，疗效确切，更好的满足临床需要。
为实现上述发明目的，本发明一方面提供一种稳定有效的盐酸曲普利啶口服溶液，由盐酸曲普利啶，氢溴酸右美沙芬、盐酸去氧肾上腺素、药学上可接受的pH调节剂、抑菌剂、矫味剂、溶剂组成。
其中，每1ml口服溶液中包括盐酸曲普利啶0.5-1.0mg；氢溴酸右美沙芬4-10mg；盐酸去氧肾上腺素2-5mg。
本发明的口服溶液pH为5-7，优选pH为6-7，更优选pH为6.3。本发明人发现盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素在不同的pH条件下稳定性差异较大，尤其在使用某些缓冲液作为pH调节剂的情况下，所述缓冲液在低含量使用，用量刚好足以获得和保持所期望的pH时，样品更加稳定。
所述的pH调节剂可以是有机或无机可食用酸，该酸可以是其未解离的形式或者可供选择的以其各自盐的形式存在。以上pH调节剂可以是柠檬酸、枸橼酸、酒石酸、富马酸、苹果酸、马来酸、盐酸、氢氧化钠、磷酸及其盐形式中的一种或者几种。优选的pH调节剂为柠檬酸及柠檬酸钠。
所述的抑菌剂为山梨酸、丙二醇、山梨酸钾、苯甲酸、苯甲酸钠、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲醇、苯扎氯铵、苯扎溴铵中的一种或者几种。优选抑菌剂为山梨酸、丙二醇、山梨酸钾。
所述的溶液剂可任选地包含糖和/或其它甜味剂，以提供甜味和对药物活性物质的掩味作用，以及提供一定的浓郁性和稠密度。可选择的甜味剂为蔗糖、三氯蔗糖、甜菊素、糖精钠、山梨醇、麦芽糖醇和甘露糖醇中的一种或者几种；同时溶液中加入美化剂香精，增加芳香气味，可选择的香精为什锦水果香精、草莓香精、橙子香精、菠萝香精、苹果香精、樱桃香精、柠檬香精、薄荷香精、泡泡糖香精中的一种或者几种。
该溶液剂包含溶剂，所述的溶剂由水、乙醇、丙二醇、甘油中一种或者几种。优选水、丙二醇、甘油组成复合溶剂。
本发明另一方面提供一种复方盐酸曲普利啶口服溶液的制备方法，包括如下顺序进行：取适量纯化水于配液桶中，加入处方量pH调节剂，搅拌溶解后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素搅拌溶解；加入pH调节剂溶解完全后，依次加入天菊素、山梨醇搅拌溶解，再依次加入甘油、丙二醇、香精搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解。测定pH，控制pH范围在5～7，采用纯化水定容至足量后过滤、灌装。
本发明的复方盐酸曲普利啶口服液澄明度高，甜口味适宜，可以准确分剂量，服用方便。
本发明的复方盐酸曲普利啶口服液稳定性高，辅料枸橼酸与其盐的形式组成的缓冲系统，使产品的pH值稳定，显著降低了化学降解。
本发明的复方盐酸曲普利啶口服溶液制备工艺简单，质量可控，生产成本低廉，适合大生产。
具体实施方式
实施例1
| 原辅料 | 剂量(g) |
| 盐酸曲普利啶 | 0.938 |
| 氢溴酸右美沙芬 | 9.25 |
| 盐酸去氧肾上腺素 | 4.56 |
| 甘油 | 125 |
| 丙二醇 | 235 |
| 山梨醇 | 100 |
| 柠檬酸 | 1.9 |
| 柠檬酸钠 | 1.0 |
| 甜菊素 | 0.2 |
| 山梨酸钾 | 1.0 |
| 橙味香精 | 1.0 |
| 麦芽糖醇液 | 0.6 |
| 纯化水 | 至1000ml |
制备工艺：
1、取口服液总体积65％的纯化水于配液桶中，加入处方量柠檬酸钠搅拌后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素搅拌溶解；加入柠檬酸溶解完全后，依次加入甜菊素、山梨醇搅拌溶解，再依次加入甘油、丙二醇、香精，搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解；
2、用20％柠檬酸溶液或20％柠檬酸钠溶液调节pH值至6.101；
3、采用纯化水定容至足量
4、先采用孔径为5μm的混合膜过滤，再用孔径为0.8μm的混合膜进行第二次过滤；
5、取样检测中间体，同时观察性状、测定pH；
6、中间体检测合格后灌装。
实施例2
| 原辅料 | 剂量(g) |
| 盐酸曲普利啶 | 0.5 |
| 氢溴酸右美沙芬 | 4 |
| 盐酸去氧肾上腺素 | 2 |
| 甘油 | 125 |
| 丙二醇 | 235 |
| 山梨醇 | 100 |
| 柠檬酸 | 2.0 |
| 柠檬酸钠 | 1.0 |
| 甜菊素 | 0.2 |
| 山梨酸钾 | 1.0 |
| 草莓香精 | 1.0 |
| 麦芽糖醇液 | 0.6 |
| 纯化水 | 至1000ml |
1、取口服液总体积65％的纯化水于配液桶中，加入处方量柠檬酸钠搅拌后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素搅拌溶解；加入柠檬酸溶解完全后，依次加入甜菊素、山梨醇搅拌溶解，再依次加入甘油、丙二醇、香精，搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解；
2、用20％柠檬酸溶液或20％柠檬酸钠溶液调节pH值至6.0；
3、采用纯化水定容至足量
4、先采用孔径为5μm的混合膜过滤，再用孔径为0.8μm的混合膜进行第二次过滤；
5、取样检测中间体，同时观察性状、测定pH；
6、中间体检测合格后灌装。
实施例3
| 原辅料 | 剂量(g) |
| 盐酸曲普利啶 | 0.938 |
| 氢溴酸右美沙芬 | 9.25 |
| 盐酸去氧肾上腺素 | 4.56 |
| 甘油 | 250 |
| 丙二醇 | 235 |
| 山梨醇 | 100 |
| 柠檬酸 | 1.9 |
| 柠檬酸钠 | 1.0 |
| 三氯蔗糖 | 0.2 |
| 尼泊金甲酯 | 0.1 |
| 尼泊金丙酯 | 0.1 |
| 草莓香精 | 1.0 |
| 麦芽糖醇液 | 0.6 |
| 纯化水 | 至1000ml |
1、取口服液总体积65％的纯化水于配液桶中，加入处方量柠檬酸钠搅拌后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素搅拌溶解；加入柠檬酸溶解完全后，依次加入甜菊素、山梨醇搅拌溶解，再依次加入甘油、丙二醇、香精，搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解；
2、用20％柠檬酸溶液或20％柠檬酸钠溶液调节pH值至6.1；
3、采用纯化水定容至足量
4、先采用孔径为5μm的混合膜过滤，再用孔径为0.8μm的混合膜进行第二次过滤；
5、取样检测中间体，同时观察性状、测定pH；
6、中间体检测合格后灌装。
实施例4
| 原辅料 | 剂量(g) |
| 盐酸曲普利啶 | 0.938 |
| 氢溴酸右美沙芬 | 9.25 |
| 盐酸去氧肾上腺素 | 4.56 |
| 甘油 | 125 |
| 丙二醇 | 235 |
| 山梨醇 | 100 |
| 甜菊素 | 0.2 |
| 山梨酸钾 | 1.0 |
| 草莓香精 | 1.0 |
| 麦芽糖醇液 | 0.6 |
| 纯化水 | 至1000ml |
制备工艺：
1、取口服液总体积65％的纯化水于配液桶中，加入处方量柠檬酸钠搅拌后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素搅拌溶解；加入柠檬酸溶解完全后，依次加入甜菊素、山梨醇搅拌溶解，再依次加入甘油、丙二醇、香精，搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解；
2、用20％柠檬酸溶液或20％柠檬酸钠溶液调节pH值至6.4；
3、采用纯化水定容至足量
4、先采用孔径为5μm的混合膜过滤，再用孔径为0.8μm的混合膜进行第二次过滤；
5、取样检测中间体，同时观察性状、测定pH；
6、中间体检测合格后灌装。
实施例5
1、取口服液总体积65％的纯化水于配液桶中，加入处方量柠檬酸钠搅拌后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素搅拌溶解；加入柠檬酸溶解完全后，依次加入甜菊素、山梨醇搅拌溶解，再依次加入甘油、丙二醇、香精，搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解；
2、用20％柠檬酸溶液或20％柠檬酸钠溶液调节pH值至6.5；
3、采用纯化水定容至足量
4、先采用孔径为5μm的混合膜过滤，再用孔径为0.8μm的混合膜进行第二次过滤；
5、取样检测中间体，同时观察性状、测定pH；
6、中间体检测合格后灌装。
将以上各实施例样品与HISTEX分别放置于光照(4500±500lx)、高温60℃、40℃条件下进行初步稳定性试验，结果表明：当pH＝6时，杂质增长较少，说明本发明的产品稳定性较高。试验结果如下表：
以上仅是本发明的优选实施方式，并不用以限制本发明，对于本领域技术人员来说，在不脱离本发明原理的前提下，还可以做出的若干改进、润饰、等同替换，均应包含在本发明保护范围之内。
Claims (9)
1.一种复方口服溶液剂，其特征在于：所述的溶液剂包括：盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素、药学上可接受的pH调节剂、抑菌剂、矫味剂以及药学上适宜的溶剂。
2.根据权利要求1所述的口服溶液，其特征在于：每1ml口服溶液剂中包括盐酸曲普利啶0.5-1.0mg；氢溴酸右美沙芬4-10mg；盐酸去氧肾上腺素2-5mg。
3.根据权利要求1所述的口服溶液剂，其特征在于：所述的复方口服溶液pH为5-7。
4.根据权利要求3所述的口服溶液剂，其特征在于：所述的复方口服溶液pH为6.3。
5.根据权利要求1所述的口服溶液剂，其特征在于：所述的pH调节剂可以选自柠檬酸、枸橼酸、酒石酸、富马酸、苹果酸、马来酸、盐酸、氢氧化钠、磷酸及其盐中的一种或者几种。
6.根据权利要求1所述的口服溶液剂，其特征在于：所述的抑菌剂为山梨酸、丙二醇、山梨酸钾、苯甲酸、苯甲酸钠、尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、苯甲醇、苯扎氯铵、苯扎溴铵中的一种或者几种。优选抑菌剂为山梨酸、丙二醇、山梨酸钾。
7.根据权利要求1所述的口服溶液剂，其特征在于：矫味剂为蔗糖、三氯蔗糖、甜菊素、糖精钠、山梨醇、麦芽糖醇和甘露糖醇中的一种或者几种，矫味香精选自什锦水果香精、草莓香精、橙子香精、苹果香精、樱桃香精、柠檬香精、薄荷香精、泡泡糖香精中的一种或者几种。
8.根据权利要求1所述的口服溶液剂，其特征在于：溶剂选自水、乙醇、丙二醇、甘油中一种或者几种。
9.一种复方盐酸曲普利啶口服溶液剂的制备方法，其特征在于：取适量纯化水于配液桶中，加入处方量pH调节剂，搅拌溶解后加入处方量盐酸曲普利啶、氢溴酸右美沙芬、盐酸去氧肾上腺素；搅拌溶解后加入pH调节剂，溶解完全后依次加入矫味剂、抑菌剂搅拌溶解，再依次加入甘油、丙二醇、香精搅拌至溶液澄清，最后加入山梨酸钾和麦芽糖醇液搅拌溶解，控制pH范围在5～7，采用纯化水定容至足量后过滤、灌装。
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| CN110302149A (zh) * | 2019-08-07 | 2019-10-08 | 北京博达绿洲医药科技研究有限公司 | 一种适合4-11岁儿童服用抗感冒药物及其制备方法 |
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| CN110302149A (zh) * | 2019-08-07 | 2019-10-08 | 北京博达绿洲医药科技研究有限公司 | 一种适合4-11岁儿童服用抗感冒药物及其制备方法 |
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| CN114159387B (zh) * | 2021-12-10 | 2022-08-19 | 江苏汉晨药业有限公司 | 一种氢溴酸右美沙芬口服溶液 |
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