CN107998074A - 普瑞巴林口服溶液及其制备方法 - Google Patents
普瑞巴林口服溶液及其制备方法 Download PDFInfo
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- CN107998074A CN107998074A CN201711327161.1A CN201711327161A CN107998074A CN 107998074 A CN107998074 A CN 107998074A CN 201711327161 A CN201711327161 A CN 201711327161A CN 107998074 A CN107998074 A CN 107998074A
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- pregabalin
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- 229960001233 pregabalin Drugs 0.000 title claims abstract description 60
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract
本发明涉及一种普瑞巴林口服溶液及其制备方法，本发明所述口服液体制剂含有普瑞巴林、防腐剂、缓冲剂和矫味剂等组分，本发明采用水作为溶剂，通过各组分的定量配比及协同作用，使本发明口服液体制剂具有好的稳定性，同时口味得到好的改善，患者的生存质量及用药顺应性也得到有效的改善，且口服液体制剂生物利用度明显高于固体制剂，更适于老人或儿童服用。
Description
技术领域
本发明涉及一种含有普瑞巴林的口服液体制剂，属于药物制剂领域。
背景技术
神经病理性疼痛是指由于神经***受到损伤或产生病变而导致的疼痛，以钝痛、灼热、刺痛为主要特征。癫痫-神经***常见疾病之一，是一种慢性、反复发作的短暂脑功能失调综合征，无论在发达国家还是发展中国家，癫痫都是一项重要的公共卫生问题。带状疱疹是一种急性皮肤黏膜感染的疾病，是由水痘-带状疱疹病毒引起，导致皮肤水泡簇集，易溃烂感染，而带状疱疹后神经痛是带状疱疹最严重的并发症，发作时伴有撕裂，针刺样疼痛，使患者寝食难安，而且多伴有抑郁或焦虑症状。紧张性头痛是最常见的一种头痛类型，患病率较高，患者通常感觉到钝痛，可并发失眠、抑郁及其他颅内并发症，多伴有烦躁、情绪低落等症状。上述疾病严重影响患者的身心健康和生活质量，在工作、生活上常常不能发挥正常功能。
普瑞巴林由辉瑞公司于2004年7月6日获欧洲药物管理局（EMA）批准上市，之后于2004年12月30日获美国食品药品管理局（FDA）批准作为治疗糖尿病性神经痛和带状疱疹神经痛的药物上市。普瑞巴林是美国和欧洲认可的第一个同时适用于治疗上述两种疼痛的药物。2005年6月，普瑞巴林获批用于辅助治疗成年人局部发作性癫痫，之后陆续批准治疗广泛性焦虑障碍及纤维肌痛综合征等等。新型钙离子通道调节剂普瑞巴林能够有效治疗上述疾病，改善患者的疼痛，提高睡眠质量，缓解疲劳等症状。
普瑞巴林虽然与γ-氨基丁酸（GABA）结构相似，但它与GABAA和GABAB受体的亲和力较弱。普瑞巴林在体内不会代谢为GABA或者GABA受体的拮抗剂，因此也不影响GABA的吸收或降解。研究发现，普瑞巴林与突触前神经元的电压门控性钙通道的α2-δ亚单位结合，从而导致谷氨酸和去甲肾上腺素等神经递质释放减少，通过抑制神经元兴奋、神经递质释放从而产生治疗作用。
动物实验及临床实验均表明普瑞巴林对神经病理性疼痛及附加治疗癫痫，具有显著的治疗效果，且耐受性良好，不良反应轻微。普瑞巴林作为一种化学合成的神经递质-氨基丁酸的类似物，目前主要是口给服药，具有良好的生物利用度。此外普瑞巴林还对社交焦虑障碍，不宁腿综合征，都具有较好的治疗作用，起效快，安全性好。
在世界范围内，普瑞巴林的上市产品剂型有胶囊剂、口服溶液和片剂，其中相较于口服固体制剂，口服溶液口感较好，患者顺应性更好，更适宜老年人及儿童服用。
因此，有必要提供一种安全、稳定、口感适宜、适用范围更广的普瑞巴林口服液体制备方法。
发明内容
本发明所要解决的技术问题是提供一种质量稳定、安全有效、患者顺应性强的普瑞巴林口服溶液，所述口服溶液由普瑞巴林加入下列一种或多种添加剂：防腐剂、缓冲剂、甜味剂以及芳香剂组成。
一种普瑞巴林口服液，由以下组分制备而成：普瑞巴林10-50g、防腐剂0.1-1g、磷酸盐0.1-50g、三氯蔗糖1-10g、安赛蜜2-10g、山梨醇20-45g、麦芽糖醇20-45g、食用香精0.1-10g。
本发明制备工艺如下：向配置容器中加入矫味剂和防腐剂，加入适量纯 化水溶解，再加入pH调节剂，加入普瑞巴林及芳香剂加纯化水至全量，测定pH 值，范围在pH5.0-7.0之间即可。
附图说明
图1是实施例1组与市售组大鼠血浆中普瑞巴林浓度随时间变化的情况曲线图。
具体实施方式
通过以下实施例来对本发明做进一步的具体说明，包括但不仅仅限于以下实施例。
实施例1：
处方：
普瑞巴林 20g
磷酸二氢钠 25.8g
磷酸氢二钠 0.4g
羟苯甲酯 0.13g
羟苯丙酯 0.0163g
三氯蔗糖 5g
草莓香精 2g
加水至 1000ml
向配置容器中加入三氯蔗糖5g，羟苯甲酯0.13g、羟苯丙酯0.0163g，加入适量纯化水溶解，再加入磷酸二氢钠25.8g、磷酸氢二钠0.4g，加入普瑞巴林20g及草莓香精2g，加纯化水至全量，测定pH值，范围在pH5.0-7.0之间。
实施例2：
处方：
普瑞巴林 20g
磷酸二氢钠 25.8g
磷酸氢二钠 0.4g
羟苯甲酯 0.13g
羟苯丙酯 0.0163g
安赛蜜 5g
草莓香精 1g
加水至 1000ml
向配置容器中加入安赛蜜5g，羟苯甲酯0.13g、羟苯丙酯0.0163g，加入适量纯化水溶解，再加入磷酸二氢钠25.8g、磷酸氢二钠0.4g，加入普瑞巴林20g及草莓香精1g，加纯化水至全量，测定pH值，范围在pH5.0-7.0之间。
实施例3：
处方：
普瑞巴林 20g
磷酸二氢钠 25.8g
磷酸氢二钠 0.4g
羟苯甲酯 0.13g
羟苯丙酯 0.0163g
山梨醇 40g
草莓香精 2g
加水至 1000ml
向配置容器中加入山梨醇40g，羟苯甲酯0.13g、羟苯丙酯0.0163g，加入适量纯化水溶解，再加入磷酸二氢钠25.8g、磷酸氢二钠0.4g，加入普瑞巴林20g及草莓香精2g，加纯化水至全量，测定pH值，范围在pH5.0-7.0之间。
实施例4：
处方：
普瑞巴林 20g
磷酸二氢钠 25.8g
磷酸氢二钠 0.4g
羟苯甲酯 0.13g
羟苯丙酯 0.0163g
麦芽糖醇 20g
草莓香精 2g
加水至 1000ml
向配置容器中加入麦芽糖醇20g，羟苯甲酯0.13g、羟苯丙酯0.0163g，加入适量纯化水溶解，再加入磷酸二氢钠25.8g、磷酸氢二钠0.4g，加入普瑞巴林20g及草莓香精2g，加纯化水至全量，测定pH值，范围在pH5.0-7.0之间。
效果试验例
为说明本发明的技术效果，对实施例1-4制备得到的高生物利用度普瑞巴林口服溶液做以下检测：
1 稳定性考察
1.1 普瑞巴林口服溶液影响因素试验，结果见表1：
表1影响因素试验结果
由上表可以看出，实施例1-4制得的样品，在影响因素考察中溶液均无分层、聚集、析出等现象，说明本发明制得的普瑞巴林口服溶液影响因素试验中稳定性良好。
1.2 普瑞巴林口服溶液加速试验
本发明制得的普瑞巴林口服溶液在40℃±2℃温度条件下， 分别于0月、1月、2月、3月、6月各取样一次，进行加速试验考察，结果见表2：
表2加速试验结果
由上表可以看出，经过6个月的加速试验考察，普瑞巴林口服溶液外观形状较为稳定，均为淡黄色澄清液体，pH值稳定，含量未见明显衰减，有关物质未见明显增长，表明本发明的口服液体制剂安全、稳定、可靠。
1.3 普瑞巴林口服溶液长期试验
本发明的普瑞巴林口服溶液在温度25℃±2℃、 相对湿度60%±10%条件下进行长期稳定性考察，结果见表3：
表3长期试验结果
由上表可以看出，长期稳定试验中，本发明制得的口服溶液含量稳定，没有明显下降，稳定性高，有效的保证了药品质量和患者用药的安全性。
2 大鼠给药后血药浓度实验
采用自身对照法，取50只大鼠，随机分为5组，每组10只，分别编号为实施例1-4组及原研普瑞巴林胶囊“乐瑞卡”。分别对应给予30mg/kg的普瑞巴林制剂后，测定大鼠血浆中普瑞巴林浓度随时间变化的情况。分别记录向大鼠给药后30min、60min、90min、120min、180min、240min、360min、480min、720min的血浆普瑞巴林浓度，其结果如表4所示。将实施例1组与市售普瑞巴林口服溶液组所测定大鼠血浆中普瑞巴林浓度随时间变化的情况绘制为曲线图，如图1所示。
表4 各制剂给药后不同时间血浆中普瑞巴林的浓度（单位：ng/ml）
由表4可以看出，本发明的普瑞巴林口服溶液具有良好的生物利用度，给药后在大鼠血浆中有效成分普瑞巴林的浓度明显较高，保证了其较高的生物利用度。由图1可以看出，实施例1中普瑞巴林的达峰时间前移，最高血药浓度明显增大，表明本发明的普瑞巴林口服液体制剂在生物体内可实现较快较好的吸收。
Claims (10)
1.一种普瑞巴林口服溶液，其特征在于，由以下组分制备而成：普瑞巴林、防腐剂、缓冲剂、甜味剂、芳香剂、溶剂。
2.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，含普瑞巴林10-50g、防腐剂0.1-1g、磷酸盐0.1-50g、三氯蔗糖1-10g、安赛蜜2-10g、山梨醇20-45g、麦芽糖醇20-45g、食用香精0.1-10g。
3.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，所述的防腐剂为羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯中的一种或几种混合物，优选羟苯甲酯与羟苯丙酯。
4.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，所述的缓冲剂指磷酸氢二钠-磷酸二氢钠缓冲溶液、磷酸氢二钾-磷酸二氢钾缓冲溶液、磷酸氢二钠-磷酸二氢钾缓冲溶液，其用量应控制在能使口服溶液的pH值在5.0-7.0间。
5.根据权利要求1所述的一种普瑞巴林口服液，其特征在于，所述的甜味剂是指蔗糖、葡萄糖、果糖、三氯蔗糖、安赛蜜、山梨醇、麦芽糖醇一种或几种混合物，优选三氯蔗糖。
6.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，所述的芳香剂是指草莓香精、橘子香精、柠檬香精、苹果香精、蔓越莓香精一种或几种混合物，优选草莓香精。
7.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，所述的溶剂是指水。
8.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，所口述服溶液的pH值为5.0-7.0。
9.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，所述口服溶液为真溶液、糖浆状易流动的无色至淡黄色液体。
10.根据权利要求1所述的一种普瑞巴林口服溶液，其特征在于，其制备方法如下：向配置容器中加入矫味剂和防腐剂，加入适量纯化水溶解，再加入pH调节剂，加普瑞巴林及芳香剂加纯化水至全量，测定pH值，范围在pH5.0-7.0间即可。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110693820A (zh) * | 2018-07-10 | 2020-01-17 | 北京万全德众医药生物技术有限公司 | 普瑞巴林口服溶液及其制备方法 |
| CN111855828A (zh) * | 2020-02-28 | 2020-10-30 | 中国人民解放军军事科学院军事医学研究院 | 一种同时测定普瑞巴林以及羟苯酯类抑菌剂含量的方法 |
| CN112107537A (zh) * | 2019-06-19 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | 一种普瑞巴林口服溶液及其制备方法 |
| CN112891303A (zh) * | 2021-03-24 | 2021-06-04 | 广州大光制药有限公司 | 一种普瑞巴林口服溶液及其制备方法 |
| CN113616591A (zh) * | 2021-09-03 | 2021-11-09 | 贝克诺顿(浙江)制药有限公司 | 一种普瑞巴林口服溶液及制备方法 |
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| CN1893938A (zh) * | 2003-12-18 | 2007-01-10 | 辉瑞有限公司 | 普瑞巴林组合物 |
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| CN110693820A (zh) * | 2018-07-10 | 2020-01-17 | 北京万全德众医药生物技术有限公司 | 普瑞巴林口服溶液及其制备方法 |
| CN112107537A (zh) * | 2019-06-19 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | 一种普瑞巴林口服溶液及其制备方法 |
| CN111855828A (zh) * | 2020-02-28 | 2020-10-30 | 中国人民解放军军事科学院军事医学研究院 | 一种同时测定普瑞巴林以及羟苯酯类抑菌剂含量的方法 |
| CN112891303A (zh) * | 2021-03-24 | 2021-06-04 | 广州大光制药有限公司 | 一种普瑞巴林口服溶液及其制备方法 |
| CN113616591A (zh) * | 2021-09-03 | 2021-11-09 | 贝克诺顿(浙江)制药有限公司 | 一种普瑞巴林口服溶液及制备方法 |
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