CN113616591A - 一种普瑞巴林口服溶液及制备方法 - Google Patents
一种普瑞巴林口服溶液及制备方法 Download PDFInfo
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- CN113616591A CN113616591A CN202111033379.2A CN202111033379A CN113616591A CN 113616591 A CN113616591 A CN 113616591A CN 202111033379 A CN202111033379 A CN 202111033379A CN 113616591 A CN113616591 A CN 113616591A
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- solution
- pregabalin
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- stirring
- chitosan
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Classifications
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Abstract
发明属于药物制剂领域,公开了一种具有更安全天然防腐剂的普瑞巴林口服溶液及其制备方法。该口服溶液制剂含有普瑞巴林、防腐剂、甜味剂、调味剂、pH调节剂和纯化水。所述防腐剂为壳聚糖。本发明的口服溶液具有较好的抗菌性能、口感良好、化学稳定性佳,制备工艺简单,适合工业化生产。
Description
技术领域
本发明属于医药技术领域,涉及一种可用于治疗部分神经痛和癫痫患者的普瑞巴林口服溶液及其制备方法。
背景技术
普瑞巴林(Pregabalin)是一种白色至灰白色结晶固体,化学名称为(S)-3-氨甲基-5-甲基己酸,分子式为C8H17NO2。普瑞巴林的水溶性强,脂溶性差,但其在中枢神经系统的活性很高,易于通过血脑屏障到达大脑和脊髓的作用靶点。其结构式为:
普瑞巴林是一种γ-氨基丁酸(GABA)受体激动剂,商品名LYRICA,由辉瑞公司于2004年7月6日获欧洲药物管理局(EMA)批准上市,同年获美国食品药品监督管理局(FDA)批准,临床上用于治疗与糖尿病周围神经病变相关的神经性疼痛,带状疱疹后遗神经痛、年龄1个月以上患者部分性癫痫发作的辅助疗法、纤维肌痛和与脊髓损伤相关的神经性疼痛。
普瑞巴林口服易吸收,全球上市剂型有胶囊剂、片剂和口服溶液剂,而口服溶液剂在临床上具有明显优势,尤其对于儿童及老年患者等特殊人群,能很好的解决分剂量难,服药顺应性差等问题。
专利CN107998074A公布了一种普瑞巴林口服溶液,该普瑞巴林口服液含有如下组分:甜味剂、防腐剂和缓冲剂等组分。其中甜味剂为麦芽糖醇等,防腐剂为尼泊金酯类。通过各组分的定量配比的协同作用使得口服液体制剂的生物利用度明显高于市售固体制剂。然而普瑞巴林分子中含有氨基,麦芽糖醇化学结构中含有游离的醛基或可产生醛酮互变的酮基,长期放置过程中容易与活性成分的氨基发生美拉德反应,降低活性成分的效力。此外,麦芽糖醇会与尼泊金酯类发生反应,产生杂质,降低口服液的稳定性。
专利CN110693820A公布了一种普瑞巴林口服溶液,将防腐剂、pH调节剂、甜味剂加入至60℃-80℃的热水中溶解,待溶液冷却至室温后加入普瑞巴林原料药,再将调味剂加入溶解,制备工艺较复杂。该普瑞巴林口服液的甜味剂仅使用三氯蔗糖,有效避免了与主药和防腐剂尼泊金酯产生的杂质。但是三氯蔗糖的甜度太高,容易造成服用者口味偏甜。三氯蔗糖的每日允许摄入量较低,且有报道会杀灭肠道有益菌或降低其质量。
由于普瑞巴林口服溶液本身不具有充分的抗菌效力,且为多剂量包装,为防止其在正常贮藏和多次使用过程中由于微生物污染和繁殖,使药物变质而对使用者造成危害,通常都会加入一定量的抑菌剂以保证药品的质量及安全性。
已上市的普瑞巴林口服溶液中的防腐剂均采用尼泊金酯类,然而该防腐剂存在一定的安全性问题。有研究报道尼泊金酯会在人体内累积,增加女性患乳腺癌和子宫癌的风险,在大量乳腺癌患者的病理切片中发现有尼泊金酯的残留。尼泊金酯添加在化妆品中,还会引起皮肤过敏,与紫外线接触可能会加速老化皮肤等问题。另外,尼泊金酯类水溶性差,使用时需先溶于乙醇或溶于热水,使用不方便。因此有必要寻找一种适用于普瑞巴林口服溶液,且具有优异的抗菌性和安全性的防腐剂。
专利CN112891303A公开了一种不含尼泊金酯类防腐剂的普瑞巴林口服溶液,其添加的防腐剂为枸橼酸、丙二醇和乳酸的混合物,抗菌性能优良,不易滋生病原微生物。该防腐剂能直接溶于水,使用方便,口服液的制备工艺得到了一定改善。然而丙二醇用于口服制剂,仍存在一定的毒性和刺激性。
壳聚糖(chitosan)是甲壳素脱乙酰基后的产物,是由N-乙酰-D-氨基葡萄糖单体通过β-1,4-糖苷键连接起来的直链同聚多糖,化学名是(1,4)-2-氨基-2-脱氧-β-D-葡萄糖,结构类似于纤维素,是年产量仅次于纤维素的第二大天然高分子。壳聚糖是自然界中唯一存在的碱性阳离子多糖,具有良好的生物相容性和生物可降解性,无毒无刺激。壳聚糖是一种天然的抗菌剂,具有广谱抗菌性,对大肠杆菌、荧光假单胞菌、金黄色葡萄球菌、枯草杆菌等有良好的抑制作用。壳聚糖水溶性差,但低分子量的壳聚糖可较好的溶于稀酸溶液。
本发明使用壳聚糖代替传统的防腐剂制备普瑞巴林口服溶液,口服液的稳定性和抑菌效力良好,患者的用药安全性也得到提高。
发明内容
鉴于现有技术的不足,发明人提供了一种更安全,含有天然防腐剂壳聚糖的普瑞巴林口服溶液,该口服液制备工艺简单,原辅料溶解无需热水,具有优良的化学稳定性,口感良好,患者用药依从性好。
该发明具体通过以下方案实现:
一种普瑞巴林口服溶液,所述口服溶液由普瑞巴林原料药和一定量辅料配制而成的溶液剂,所述普瑞巴林口服溶液中的辅料包括防腐剂、甜味剂、调味剂、pH调节剂和纯化水。
所述普瑞巴林在口服液中的浓度为15-25mg/ml,优选的,普瑞巴林的浓度为20mg/ml。
所述普瑞巴林口服溶液中防腐剂为壳聚糖,所述壳聚糖脱乙酰度为75%-95%,重均分子量为1500-5000。
优选的,所述普瑞巴林口服溶液中壳聚糖的浓度为0.2mg-1.0mg/ml。
所述普瑞巴林口服溶液中的甜味剂选自低聚果糖、低聚异麦芽糖、低聚木糖、甜菊苷、甜蜜素、甜菊素、安赛蜜、棉籽糖、阿斯巴甜和大豆低聚糖中的一种或两种以上的组合。
优选的,所述普瑞巴林口服溶液中甜味剂的浓度为1.0mg-10mg/ml。
所述普瑞巴林口服溶液中的调味剂选自草莓香精、橘子香精、蓝莓香精、苹果香精、柠檬香精和巧克力香精中的一种或两种以上的组合。优选的,口服溶液中调味剂的浓度为0.1mg-1.0mg/ml。
所述的普瑞巴林口服溶液中的pH调节剂选自醋酸、苹果酸、乳酸、柠檬酸、碳酸氢钠、碳酸氢钾、磷酸二氢钠和磷酸氢二钠中的一种或两种以上的组合。
所述普瑞巴林口服溶液pH值为4.0-7.5,优选的pH值为4.5-6.5,进一步优选的pH值为5.0-6.5。
在本发明优选的实施方案中,本发明提供的普瑞巴林口服溶液,其中,所用溶剂为水,其量通常是使得口服溶液的体积扩增到规定值,因此本领域技术人员在描述口服溶液中水的量时,通常不作具体描述。或者仅仅是指出其量是适量,或者指出其量是“余量”。
本发明还提供了一种普瑞巴林口服溶液的制备方法,所述方法包括以下步骤:
(1)用醋酸、苹果酸、乳酸或柠檬酸中的一种或两种以上的组合溶于水,配制成一定浓度的酸性溶液。
(2)将适量壳聚糖加入酸性溶液中搅拌溶解,加入弱碱性溶液进行快速中和,将酸性壳聚糖溶液的pH值调至pH5.0-7.5之间。优选的,碱性溶液为碳酸氢钠或枸橼酸钠溶液中的一种或两种。优选的,弱碱性溶液浓度为0.5mol/L-1.0mol/L。
(3)将甜味剂、调味剂加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解。
(4)将步骤(2)的适量溶液与步骤(3)的药液混合,搅拌均匀。
(5)任选地,用pH调节剂调节步骤(4)所得药液的pH至规定的范围。
(6)向步骤(5)所得药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,制得普瑞巴林口服溶液。
与现有技术相比,本发明具有如下优势:
(1)该口服液安全性提高,化学稳定性好。选用的防腐剂无毒、无刺激、生物相容性好,口服液中防腐剂的浓度低于原研;选用的甜味剂可有效避免与原料药产生杂质的风险。
(2)工艺简单,制备条件温和。原辅料无需用热水溶解。
具体实施方式
下面通过实施例来进一步描述本发明的有益效果,应该正确理解的是:本发明的实施例仅仅是用于说明本发明而给出,而不是对本发明的限制。所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
在下面配液制备各种组合物中,如未另外说明,列明配方和制备过程时,对于口服溶液剂,以每100ml药液中的组成阐明配方和制法。在分装时,每瓶药液量为473ml。
实施例1
1)处方
普瑞巴林2.0g
壳聚糖0.05g
甜蜜素0.25g
安赛蜜0.05g
草莓香精0.03g
苹果酸0.05g
碳酸氢钠适量
纯化水补足至100ml
2)制备工艺
(a)将处方量的苹果酸溶于25ml纯化水中,加入处方量的壳聚糖,充分搅拌使溶解;
(b)取适量1mol/L的碳酸氢钠溶液进行快速中和,调节壳聚糖溶液pH值至5.0-7.5;
(c)将处方量的甜蜜素、安赛蜜、草莓香精加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解;
(d)将壳聚糖溶液与步骤(c)的药液混合,搅拌均匀;
(e)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到pH5.0-6.5的普瑞巴林口服溶液。
实施例2
1)处方
普瑞巴林2.0g
壳聚糖0.08g
甜菊苷0.20g
蓝莓香精0.03g
柠檬酸0.06g
枸橼酸钠适量
纯化水补足至100ml
2)制备工艺
(a)将处方量的柠檬酸溶于25ml纯化水中,加入处方量的壳聚糖,充分搅拌使溶解;
(b)取适量1mol/L的枸橼酸钠溶液进行快速中和,调节壳聚糖溶液pH值至5.0-7.5;
(c)将处方量的甜菊苷、蓝莓香精加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解;
(d)将壳聚糖溶液与步骤(c)的药液混合,搅拌均匀;
(e)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到pH6.0的普瑞巴林口服溶液。
实施例3
1)处方
普瑞巴林2.0g
壳聚糖0.05g
棉籽糖0.30g
橘子香精0.03g
醋酸0.05g
磷酸二氢钠适量
磷酸氢二钠适量
枸橼酸钠适量
纯化水补足至100ml
2)制备工艺
(a)将处方量的醋酸溶于30ml纯化水中,加入处方量的壳聚糖,充分搅拌使溶解;
(b)取适量1mol/L的枸橼酸钠溶液进行快速中和,调节壳聚糖溶液pH值至5.0;
(c)将处方量的棉籽糖、橘子香精加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解;
(d)将壳聚糖溶液与步骤(c)的药液混合,搅拌均匀;
(e)将磷酸二氢钠和磷酸氢二钠配制成磷酸盐缓冲液,将混合药液的pH值调节至5.5~6.5;
(f)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到pH6.1的普瑞巴林口服溶液。
实施例4
1)处方
普瑞巴林2.0g
壳聚糖0.05g
低聚异麦芽糖0.30g
苹果香精0.03g
乳酸0.04g
磷酸二氢钠适量
碳酸氢钠适量
纯化水补足至100ml
2)制备工艺
(a)将处方量的乳酸溶于25ml纯化水中,加入处方量的壳聚糖,充分搅拌使溶解;
(b)取适量0.6mol/L的碳酸氢钠溶液进行快速中和,调节壳聚糖溶液pH值至6.5;
(c)将处方量的低聚异麦芽糖、苹果香精加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解;
(d)将壳聚糖溶液与步骤(c)的药液混合,搅拌均匀;
(e)将磷酸二氢钠配制成磷酸盐水溶液,将混合药液的pH值调节至6.0;
(f)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到pH6.1的普瑞巴林口服溶液。
实施例5
1)处方
普瑞巴林2.0g
壳聚糖0.03g
低聚果糖0.35g
草莓香精0.03g
苹果酸0.03g
醋酸0.02g
碳酸氢钠适量
纯化水补足至100ml
2)制备工艺
(a)将处方量的苹果酸和醋酸溶于25ml纯化水中,加入处方量的壳聚糖,充分搅拌使溶解;
(b)取适量1mol/L的碳酸氢钠溶液进行快速中和,调节壳聚糖溶液pH值至5.0-7.5;
(c)将处方量的低聚果糖、草莓香精加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解;
(d)将壳聚糖溶液与步骤(c)的药液混合,搅拌均匀;
(e)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到pH5.0-6.5的普瑞巴林口服溶液。
对比实施例1
1)处方
普瑞巴林2.0g
苯甲酸钠0.08g
三氯蔗糖0.03g
柠檬香精0.02g
磷酸二氢钠适量
磷酸氢二钠适量
纯化水补足至100ml
2)制备工艺
(a)将60%-80%的纯化水加热至60℃-80℃;
(b)将处方量的苯甲酸钠和三氯蔗糖加入至热水中,搅拌使溶解;
(c)待上述溶液凉至室温,加入普瑞巴林和柠檬香精搅拌溶解;
(d)上述药液中加入适量磷酸二氢钠和磷酸氢二钠,调节药液pH值至5.5;
(e)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到普瑞巴林口服溶液。
对比实施例2
3)处方
普瑞巴林2.0g
羟苯甲酯0.15g
羟苯丙酯0.02g
麦芽糖醇0.05g
蓝莓香精0.03g
磷酸二氢钠适量
磷酸氢二钠适量
纯化水补足至100ml
4)制备工艺
(a)将60%-80%的纯化水加热至60-80℃;
(b)将处方量的羟苯甲酯、羟苯丙酯和麦芽糖醇加入至热水中,搅拌使溶解;
(c)待上述溶液凉至室温,加入普瑞巴林和蓝莓香精搅拌溶解;
(d)上述药液中加入适量磷酸二氢钠和磷酸氢二钠,调节药液pH值至6.0;
(e)向混合药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,得到普瑞巴林口服溶液。
验证实施例
1.稳定性考察
为证明本发明的优越性,发明人对本发明的实施例和对比实施例中所得产品在40℃±2℃、75%±5%RH条件中存放6个月,分别于0月、1月和6月对保留样品的外观性状、pH值和有关物质进行测定。具体数据如下表所示。
表1.普瑞巴林口服溶液加速试验结果
2.抑菌效力测定
测定方法参照《中国药典》2020年版四部通则1121“抑菌效力检查法”中提供的方法。在规格为100ml的普瑞巴林口服溶液实施例1~5和对比实施例1~2中分别接种金黄色葡萄球菌、铜绿假单胞菌、大肠埃希菌、白色念珠菌和黑曲霉中的一种试验菌,接种体积为0.2ml,接种后供试液的含菌量约为105~106CFU/ml,充分混匀,使供试液中的试验菌分布均匀,25℃下避光贮存。
在各间隔时间点14天、28天分别取相应的供试液1ml,采用经方法适用性试验验证的计数方法进行存活菌数测定。结果如表2所示。
表2.普瑞巴林口服溶液抑菌效力测定结果
注:表中的“减少的1g值”是指各间隔时间测定的菌数1g值与1ml供试液中的接种菌数。
由上表结果可知,相比于对比实施例2(含尼泊金酯类防腐剂)普瑞巴林口服溶液,实施例1-5普瑞巴林口服溶液的抑菌效力能够达到相当甚至更优的效果,说明壳聚糖在普瑞巴林口服液中的抑菌效果良好,防腐效能显著。
Claims (8)
1.一种普瑞巴林口服溶液,其特征在于,所述口服溶液的组分为:普瑞巴林、防腐剂、甜味剂、调味剂、pH调节剂和纯化水。
2.根据权利要求1所述的普瑞巴林口服溶液,其特征在于,普瑞巴林的浓度为15-25mg/ml,优选的,普瑞巴林的浓度为20mg/ml。
3.根据权利要求1所述的普瑞巴林口服溶液,其特征在于,所述防腐剂为壳聚糖,所述壳聚糖脱乙酰度为75%-95%,重均分子量为1500-5000,优选的,口服溶液中壳聚糖的浓度为0.2mg-1.0mg/ml。
4.根据权利要求1所述的普瑞巴林口服溶液,其特征在于,所述甜味剂选自低聚果糖、低聚木糖、甜蜜素、甜菊苷、甜菊素、安赛蜜、棉籽糖、低聚异麦芽糖、阿斯巴甜和大豆低聚糖中的一种或两种以上的组合,优选的,口服溶液中甜味剂的浓度为1.0mg-10mg/ml。
5.根据权利要求1所述的普瑞巴林口服溶液,其特征在于,所述调味剂选自草莓香精、橘子香精、蓝莓香精、苹果香精、柠檬香精和巧克力香精中的一种或两种以上的组合,优选的,口服溶液中调味剂的浓度为0.1mg-1.0mg/ml。
6.根据权利要求1所述的普瑞巴林口服溶液,其特征在于,所述pH调节剂选自醋酸、苹果酸、乳酸、柠檬酸、碳酸氢钠、碳酸氢钾、枸橼酸钠、磷酸二氢钠和磷酸氢二钠中的一种或两种以上的组合。
7.根据权利要求1所述的普瑞巴林口服溶液,其特征在于,所述口服溶液的pH值为4.0-7.5,优选的pH值为4.5-6.5,进一步优选的pH值为5.0-6.5。
8.一种权利要求1-7任一项权利要求所述普瑞巴林口服溶液的制备方法,其特征在于,所述方法包括以下步骤:
(1)用醋酸、苹果酸、乳酸或柠檬酸中的一种或两种以上的组合溶于水,配制成一定浓度的酸性溶液;
(2)将适量壳聚糖加入酸性溶液中搅拌溶解,加入弱碱性溶液进行快速中和,将酸性壳聚糖溶液的pH值调至pH5.0-7.5之间,优选的,碱性溶液为碳酸氢钠或枸橼酸钠溶液中的一种或两种,优选的,弱碱性溶液浓度为0.5mol/L-1.0mol/L;
(3)将甜味剂、调味剂加入处方量40%-60%的水中,搅拌溶解,然后加入普瑞巴林,搅拌溶解;
(4)将步骤(2)的适量溶液与步骤(3)的药液混合,搅拌均匀;
(5)任选地,用pH调节剂调节步骤(4)所得药液的pH至规定的范围。
(6)向步骤(5)所得药液中补足处方量剩余的纯化水,搅拌使药液混合均匀,即得。
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