CN115645357B - 一种拉考沙胺口服溶液处方及其制备工艺 - Google Patents
一种拉考沙胺口服溶液处方及其制备工艺 Download PDFInfo
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Abstract
本发明公开了一种拉考沙胺处方及其制备工艺,具体涉及一种拉考沙胺口服溶液处方及其制备工艺,所述拉考沙胺口服溶液包含拉考沙胺、增溶剂、增稠剂、防腐剂、氯化钠、酸度调节剂、以及必要的矫味剂和水;本发明的口服溶液便于分装,通过调整增稠剂与拉考沙胺的相对含量,在减少甜味剂和矫味剂用量的情形下,增加口服溶液的粘度,可减少原料药带来的苦味,特别适合儿童尤其是4岁以上儿童使用。
Description
技术领域
本发明涉及医药领域,特别是涉及一种拉考沙胺口服溶液处方及其制备工艺。
背景技术
拉考沙胺又称拉科酰胺(Lacosamide),是优时比公司(UCB)开发的一种新型NMDA受体甘氨酸位点结合拮抗剂,在中国主要用于16岁及以上青少年和成人癫痫患者有或无继发性全面发作的部分癫痫发作的治疗辅助治疗药物,市售剂型包括薄膜衣片和注射液剂型,其有效成分拉考沙胺的IUPAC名称为(R)-2-乙酰氨基-N-苄基-3-甲氧基丙胺,化学式如下所述:
,CAS RN为175481-36-4。拉考沙胺是一种功能化氨基酸,原料药白色到浅黄色的粉末,它少量溶于水,微溶于乙腈和乙醇。
市售拉考沙胺薄膜衣片含有以下非活性成分:胶体二氧化硅、交联聚维酮、羟丙基纤维素、羟丙甲纤维素、卵磷脂、硬脂酸镁、微晶纤维素、聚乙二醇、聚乙烯醇、滑石粉、二氧化钛和染色剂,规格分别为50 mg,100 mg,150 mg和200 mg。
市售拉考沙胺注射液是一种透明、无色的无菌溶液,每毫升含有10毫克拉考沙胺,用于静脉输液,每个20毫升的小瓶含有200毫克拉可沙胺原料药;非活性成分是氯化钠和注射用水,盐酸用于调节pH值至3.5至5.0。
以上剂型对于16岁以上的青少年和成人而言是合适的,但是对儿童患者,一方面不容易依据体重精确控制给药剂量,影响治疗效果;另外一方面拉考沙胺苦味极重,不利于儿童患者服用。通过制剂学手段掩盖药物的苦味是改善儿童服药依从性和临床合理用药的重要策略,将拉考沙胺制成口服溶液可以有效解决片剂口感差和不易精确控制给药剂量的问题。但由于拉考沙胺和制备口服溶液的某些辅料在水中难以溶静置后浓度不均匀,制备工艺有一定复杂性,且制剂已知杂质较多,难以制得符合相关标准的口服溶液。发明专利申请202011044027.2公开了一种拉考沙胺口服溶液,其解决了部分控制给药剂量的问题;本申请的申请人测试其效果,发现虽然该专利申请在口服液中添加了大量的甜味剂和矫味剂,由于儿童对于苦味比成人更加敏感,其并没有将原料药的苦味遮蔽到可以接受的程度,大部分儿童仍然存在严重的服药困难问题。
发明内容
为解决上述技术问题,本发明采用的一个技术方案是 :提供一种适合4岁以下儿童使用的拉考沙胺口服溶液,该拉考沙胺口服溶液包含拉考沙胺,优选的本发明的口服溶液多剂量包含2.00 g拉考沙胺。
本发明的拉考沙胺口服溶液进一步包含增稠剂、甜味剂、掩味剂、酸度调节剂(即pH调节剂)、防腐剂以及余量的水,其特征在于所述增稠剂选自增稠剂A与甘油、聚乙二醇的组合,优选的所述增稠剂A选自羧甲基纤维素钠、羧甲基纤维素或聚乙烯吡咯烷酮(polyvinyl pyrrolidone)中的一种或多种。优选的,所述拉考沙胺与增稠剂A的质量比为1:0.2-0.4,优选为1:0.25-0.35,最优选为1:0.28-0.3。
所述拉考沙胺与甘油、聚乙二醇的质量比优选为1:6.5-7.5:6-7
本发明的甜味剂选自山梨醇、乙酰磺胺酸钾、三氯蔗糖中的一种或其组合,优选的甜味剂选自山梨醇、乙酰磺胺酸钾和三氯蔗糖的组合,所述拉考沙胺与山梨醇、乙酰磺胺酸钾、三氯蔗糖的质量比为1:(18-20):(2.4-2.7):(0.001-0.0015)
本发明的掩味剂选自氯化钠、液体掩味香精或其组合,优选的所述掩味剂选自氯化钠和液体掩味香精的组合,所述液体掩味香精选自液体草莓香精、苹果香精、橘子香精、樱桃粉末和香蕉香精中的一种或多种。优选的所述拉考沙胺与氯化钠、液体掩味香精的质量比为1:(0.13-0.15):(0.015:0.025)
本发明的pH调节剂选自无机碱和有机弱酸的组合,优选的所述无机碱选自氢氧化钠或氢氧化钾,所述有机弱酸选自枸橼酸、苹果酸、酒石酸中的一种或多种,优选的所述pH调节剂的pH调节范围为4.0-5.0。优选的所述pH调节剂选自氢氧化钠和枸橼酸的组合,所述拉考沙胺、氢氧化钠和枸橼酸的质量比为1:(0.05-0.07):(0.17-0.20)
本发明的防腐剂选自羟苯酯类、苯甲酸及其盐、山梨酸及其盐中的一种或多种,优选为羟苯甲酯;所述拉考沙胺与防腐剂的质量比优选为1:0.2-0.3,更优选为1:0.2-0.25。
优选的,本发明的拉考沙胺口服溶液单剂量配方由以下组分组成:拉考沙胺2.00g,羧甲基纤维素钠0.56g,甘油14.8g,聚乙二醇4000 12.8g,山梨醇37.4g,乙酰磺胺酸钾0.542g,三氯蔗糖0.0022g,氢氧化钠0.1168g,无水枸橼酸0.365g,氯化钠0.284g,液体草莓香精0.004g,羟苯甲酯0.444g,余量的水至200ml。
优选的,本发明的拉考沙胺口服溶液单剂量配方由以下组分组成:拉考沙胺2.00g,羧甲基纤维素钠0.46g,甘油13.0g,聚乙二醇4000 14.0g,山梨醇37.4g,乙酰磺胺酸钾0.542g,三氯蔗糖0.0022g,氢氧化钠0.1168g,无水枸橼酸0.365g,氯化钠0.284g,液体草莓香精0.004g,羟苯甲酯0.444g,余量的水至200ml。
优选的,本发明的拉考沙胺口服溶液单剂量配方由以下组分组成:拉考沙胺2.00g,羧甲基纤维素钠0.66g,甘油14.00g,聚乙二醇4000 13.6g,山梨醇37.4g,乙酰磺胺酸钾0.542g,三氯蔗糖0.0022g,氢氧化钠0.1168g,无水枸橼酸0.365g,氯化钠0.284g,液体草莓香精0.004g,羟苯甲酯0.444g,余量的水至200ml。
更优选的本发明的拉考沙胺口服溶液单剂量配方由以下组分组成:拉考沙胺2.00g,羧甲基纤维素钠0.76g,甘油15.0g,聚乙二醇4000 12.0g,山梨醇37.4g,乙酰磺胺酸钾0.542g,三氯蔗糖0.0022g,氢氧化钠0.1168g,无水枸橼酸0.365g,氯化钠0.284g,液体草莓香精0.004g,羟苯甲酯0.444g,余量的水至200ml
对于本发明所提到的术语枸橼酸,其可以为无水枸橼酸,也可以为枸橼酸一水合物或者二者的混合物。
本发明的有益效果:
针对现有技术中拉考沙胺临床使用中的问题,提供一种拉考沙胺口服溶液,该口服液便于精确控制给药剂量,可以方便的依据儿童的体重调节使用剂量,且性质稳定,杂质含量符合相关标准。
申请人猜测,通过加入了较高量的羧甲纤维素钠与甘油、聚乙二醇配伍,增加了产品粘度,降低主成分在味蕾中的扩散速度,从而抑制本品在服用时的苦味。同时本品添加了山梨醇、氯化钠、乙酰磺胺酸钾、三氯蔗糖和两种香精作为掩味剂和甜味剂,从而进一步抑制本品的苦味,提高儿童患者的临床适用性。
本发明通过采用提高增稠剂羧甲基纤维素的相对用量,减少了甜味剂和矫味剂的使用,羧甲基纤维素钠对人体无毒无副作用,对改善儿童服药依从性和临床用药合理性的效果显著,更加方便4岁以上癫痫患者或儿童患者使用,治疗效果更好。
实施方式
通用制备例:
拉考沙胺口服溶液的制备方法包括:按比例称量原料药和各种辅料备用,然后(1)将羧甲纤维素钠分散在甘油中后加至纯化水中搅拌分散,再加入部分纯化水搅拌至溶解,(2)加入聚乙二醇4000和山梨醇,(3)加入拉考沙胺、羟苯甲酯、氯化钠和乙酰磺胺酸钾,(5)冷却溶液,(6)加入氢氧化钠、无水枸橼酸、三氯蔗糖、液体草莓香精和剩余量的纯化水,(7)药液过滤至灌装线,(8)灌装。药液装量为200ml,所用容器为200ml棕色聚酯瓶。
实施例1:
本部分包含对拉考沙胺口服溶液(200ml :2g)的药物组成的描述:
实施例2:
本部分包含对拉考沙胺口服溶液(200ml :2g)的药物组成的描述:
实施例3:
本部分包含对拉考沙胺口服溶液(200ml :2g)的药物组成的描述:
实施例4:
本部分包含对拉考沙胺口服溶液(200ml :2g)的药物组成的描述:
实施例5和对比例1:
本部分包含对拉考沙胺口服溶液(1000ml :10g)的药物组成以及对比例的描述以及稳定性研究:
测试例1:苦味测试
儿童对于苦味、辣味等刺激性味道更为敏感,儿童用药需对药品进行苦味测试以判断依从性;鉴于儿童对于苦味的描述可能不如成人客观,因此在苦味测试选用健康的成人志愿者入组测试,年龄为18-35岁,数目为100人,男女各半。
测试对象为本申请实施例1制备得到的拉考沙胺口服溶液和依据发明专利申请CN202011044027.2实施例1制备得到的拉考沙胺口服溶液。
测试方法为分别给予志愿者上述一种口服溶液2 ml品尝,5秒后吐出,10ml纯净水漱口3次,漱口后等待10分钟后给予另外一种口服溶液2 ml品尝,5秒后吐出。测试时志愿者不得知晓两种溶液的来源,医生知晓并记录统计。
统计标准为A微苦;B更苦。
测试结果:经统计,82名志愿者反应本申请实施例1制备得到的拉考沙胺口服溶液为A微苦,CN202011044027.2实施例1制备得到的拉考沙胺口服溶液为B更苦;18名志愿者反应本申请实施例1制备得到的拉考沙胺口服溶液为A微苦,CN202011044027.2实施例1制备得到的拉考沙胺口服溶液为B更苦。以上数据反应本申请制备得到的口服液具备更好的临床使用依从性。
测试例2:加速试验稳定性测试:
三氯蔗糖作为一种高甜度、低热量、无毒、无刺激、较稳定的甜味剂,被广泛用于饮料、食品和药品中。较传统甜味剂相比,三氯蔗糖不会引起血糖波动,也不增加热量的摄入。较一些新型甜味剂相比,如阿斯巴甜在人体内会分解产生苯丙氨酸,不适用于苯丙酮尿症患者使用,而三氯蔗糖则具有体内吸收差、代谢速率快、不易在体内积累的特点,只有少量会被分解,产物对人体不会产生伤害,因此三氯蔗糖更加安全可靠。同时,三氯蔗糖较阿巴斯甜相比热稳定更好。本发明同时也测试了实施例1所得产品原料药和阿巴斯甜在加速试验条件下相对于起始时间的相对含量,测试条件和测试结果如下所述:
试验条件:加速试验条件为40℃±2℃/75%RH±5%RH,考察时间为6个月,在试验期间第1、2、3、6个月月末分别取样进行测试,以起始时间点原料药和三氯蔗糖的相对含量为100%计,检测原料药和三氯蔗糖相对于起始(0个月)时间点的相对含量;检测采用HPLC(内标法),色谱柱:YMC-Pack ODS C18 150 × 4.6mm,5μm,低温型蒸发光散射检测器:SEDEXLT-ELSD
以上数据表明本发明实施例1所得拉考沙胺口服溶液中的原料药和三氯蔗糖在加速试验条件下可以保持较好的稳定性。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (2)
1.一种拉考沙胺口服溶液,所述的口服溶液由原料药拉考沙胺、增稠剂、甜味剂、掩味剂、酸度调节剂、防腐剂以及余量的水组成,且所述增稠剂为增稠剂A与甘油、聚乙二醇的组合,其特征在于:
所述拉考沙胺与增稠剂A的质量比为1:0.28,所述拉考沙胺与甘油、聚乙二醇的质量比为1:6.5-7.5:6-7;所述增稠剂A选自羧甲基纤维素钠;
所述的甜味剂选自山梨醇、乙酰磺胺酸钾、三氯蔗糖中的组合;所述拉考沙胺与山梨醇、乙酰磺胺酸钾、三氯蔗糖的质量比为1:(18-20):(2.4-2.7):(0.001-0.0015);
所述防腐剂选自羟苯甲酯,所述拉考沙胺与防腐剂的质量比为1:0.2-0.25;
所述的掩味剂选自氯化钠、液体掩味香精或其组合,所述拉考沙胺与氯化钠、液体掩味香精的质量比为1:(0.13-0.15):(0.015-0.025);
所述的酸度调节剂选自无机碱和有机弱酸的组合,所述酸度调节剂的pH调节范围为5.5-7.5。
2.一种拉考沙胺口服溶液,其特征在于所述拉考沙胺口服溶液的单剂量配方由以下组分组成:拉考沙胺2.00g,羧甲基纤维素钠0.56g,甘油14.8g,聚乙二醇4000 12.8g,山梨醇37.4g,乙酰磺胺酸钾0.542g,三氯蔗糖0.0022g,氢氧化钠0.1168g,无水枸橼酸0.365g,氯化钠0.284g,液体草莓香精0.04g,羟苯甲酯0.444g,余量的水至200ml。
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