CN107137374B - 帕洛诺司琼的固体药物组合物 - Google Patents
帕洛诺司琼的固体药物组合物 Download PDFInfo
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- CN107137374B CN107137374B CN201710478333.9A CN201710478333A CN107137374B CN 107137374 B CN107137374 B CN 107137374B CN 201710478333 A CN201710478333 A CN 201710478333A CN 107137374 B CN107137374 B CN 107137374B
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- Prior art keywords
- palonosetron
- pharmaceutical composition
- pharmaceutically acceptable
- solid pharmaceutical
- acceptable salt
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 239000007787 solid Substances 0.000 title claims abstract description 22
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- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 claims description 19
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Abstract
本发明涉及一种帕洛诺司琼的固体药物组合物，其包括帕洛诺司琼或其可药用盐和药学上可接受的赋形剂，其中不含粘合剂。
Description
本申请是申请号为201210186522.6，申请日为2012年6月2日，发明名称为“帕洛诺司琼的固体药物组合物”的分案申请。
技术领域
本发明涉及药物组合物，具体地说，本发明涉及一种治疗癌症化疗药物引起的恶心、呕吐的含有5-HT3受体拮抗剂的口服药物组合物及其制备方法及其在医药领域的用途。
背景技术
帕洛诺司琼(Palonosetron)具有如式Ⅰ所示的结构式，化学名为(3aS)-2-[(3s)-1-氮杂双环[2.2.2]辛烷基-2,3,3a,4,5,6-六氢-1-氧代-1H-苯并[de]异喹啉，是由Helsinn公司开发的选择性5-HT3受体拮抗剂。帕洛诺司琼盐酸盐注射液于2003年获得美国食品与药物管理局(FDA)批准，用于治疗中度或高度致呕性化疗引发的急性和迟发行恶心呕吐。
治疗恶心呕吐的药物在用药时需要起效快并具有高的生物利用度，因此现有技术常将帕洛诺司琼制备成注射剂，但注射剂存在稳定性等问题，现有技术有公开通过调节pH范围为4.0-6.0并添加甘露醇和螯合剂来提高注射剂的稳定性(CN1758911)。
为了进一步提高帕洛诺司琼注射剂的稳定性，现有技术还公开了软胶囊制剂，如CN101573106公开了一种帕洛诺司琼软胶囊制剂，该发明通过采用氧的渗透率小于约1.0×10-3ml·cm/(cm2·24hr.atm)的明胶软外壳、以及选择性地加入抗氧化剂以获得高稳定性的帕洛诺司琼口服制剂。
WO2010077669公开了一种稳定的帕洛诺司琼固体制剂。在优选的方式中固体制剂是一种硬胶囊剂，包括帕洛诺司琼或其盐、稀释剂、粘合剂、崩解剂、润滑剂，优选的制剂中不包含抗氧剂。该发明解决了一定的处分分散均匀度、药物溶出及生物利用度的问题，但处方复杂，为了进一步达到帕洛诺司琼起效快、生物利用度高的要求，需要开发一种具有更快溶出速度和高生物利用度的稳定的帕洛诺司琼固体制剂。
发明内容
本发明提供一种帕洛诺司琼的固体药物组合物，其包括帕洛诺司琼或其可药用盐和药学上可接受的赋形剂，其中不含粘合剂。
本发明还提供一种帕洛诺司琼的固体药物组合物，其由帕洛诺司琼或其可药用盐、稀释剂、崩解剂和润滑剂组成。
帕洛诺司琼可药用盐包括无机酸盐和有机酸盐，无机酸盐例如可以是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等，有机酸盐例如可以是乙酸盐、丙酸盐、丁酸盐、戊酸盐、己酸盐、庚酸盐、环戊酸盐、环己酸盐、乙二酸盐、丙酮酸盐、乳酸盐、丙二酸盐、琥珀酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、肉桂酸盐、苯基乙酸盐、甲磺酸盐、乙磺酸盐、月桂硫磺酸盐、葡萄糖酸盐、谷氨酸盐、水杨酸盐、硬脂酸盐、己二烯二酸盐等。其中优选为帕洛诺司琼盐酸盐。
本发明所述的稀释剂选自乳糖、微晶纤维素、淀粉、预胶化淀粉、蔗糖、葡萄糖、甘露醇、山梨醇、木糖醇、糊精、硫酸钙、磷酸氢钙、磷酸二钙、一水磷酸钙、纤维素、乙基纤维素、白陶土、碳酸钙、碳酸镁、轻质氧化镁中的任意一种或多种的混合物，优选为乳糖、微晶纤维素中任意一种或两种的混合物。
本发明所述的稀释剂与帕洛诺司琼或其可药用盐(以帕洛诺司琼计)的重量比为50～1000:1，优选为100～500:1，更优选为100～400:1。
本发明所述的崩解剂选自羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮、淀粉、羧甲基淀粉纳、羟丙基淀粉、低取代羟丙基纤维素、硅酸镁铝、重碳酸钠、乙醇酸淀粉钠、海藻酸、海藻酸钠、酒石酸、柠檬酸、碳酸氢钠、碳酸钠、聚山梨醇酯80、十二烷基硫酸钠中的任意一种或多种的混合物，优选为羧甲基淀粉纳、交联聚维酮，更优选为羧甲基淀粉纳。
本发明所述的崩解剂与帕洛诺司琼或其可药用盐(以帕洛诺司琼计)的重量比为5～30:1，优选为5～20:1，更优选为10～15:1。
本发明所述的润滑剂为硬脂酸、硬脂酸钙、硬脂酸镁、滑石粉、微粉硅胶、聚乙二醇、单硬脂酸甘油酯、十二烷基硫酸镁、十二烷基硫酸钠、苯甲酸钠中的任意一种或多种的混合物，优选为硬脂酸镁。
本发明所述的润滑剂与帕洛诺司琼或其可药用盐(以帕洛诺司琼计)的重量比为0.1～10:1，优选为0.5～5:1，更优选为1～2:1。
本发明的固体药物组合物可以为胶囊剂、片剂、颗粒剂，优选为硬胶囊制剂。
作为另一种优选的方式，本发明的固体药物组合物是由帕洛诺司琼或其可药用盐、乳糖、微晶纤维素、羧甲基淀粉钠和硬脂酸镁组成的硬胶囊剂。
含有本发明的固体药物组合物的制剂规格为0.25mg、0.5mg、0.75mg，即每单位制剂中可以含有0.25mg、0.5mg或0.75mg的帕洛诺司琼。
同时，本发明还提供一种帕洛诺司琼的固体药物组合物的制备方法，该方法包括将帕洛诺司琼或其可药用盐和药学上可接受的赋形剂均匀混合，然后使用公知的制剂方法制成颗粒剂、片剂或胶囊，其中药学上可接受的赋形剂不含粘合剂。
本发明还提供一种帕洛诺司琼的固体药物组合物的制备方法，该方法包括将帕洛诺司琼或其可药用盐、稀释剂、崩解剂和润滑剂均匀混合，然后使用公知的制剂方法制成颗粒剂、片剂或胶囊。
本发明还提供一种帕洛诺司琼的固体药物组合物的制备方法，该方法包括将帕洛诺司琼或其可药用盐与乳糖、微晶纤维素、羧甲基淀粉钠、硬脂酸镁均匀混合，作为中间体，然后取中间体样品适量，检测水分、药物含量，根据中间体的药物含量填充硬胶囊，并检验、包装。
以上制备方法中的混合可以是直接混合、湿法制粒混合、干法制粒混合、等量递加混合等本领域人员公知的混合方式，或者是将原料药和/或赋形剂粉碎后再混合均匀。
另外，本发明还提供帕洛诺司琼的固体药物组合物在制备预防和治疗呕吐的药物中的应用。
本发明提供的洛诺司琼的固体药物组合物，处方工艺简单，稳定性好，对氧含量和氧渗透率无过高要求，适合工业化大生产。而且本发明的帕洛诺司琼固体药物组合物，不仅具有与液体制剂如注射液相当的高生物利用度，而且溶出速度更快，在对患者用药时起效更快，能更快更好地发挥疗效。
具体实施方式
以下通过实施例进一步阐述本发明，但本发明并不局限于这些实施例。
实施例1帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼，加入5倍量乳糖混合后进行气流粉碎，再向所得混合粉末中加入5倍乳糖混合均匀，然后再将剩余乳糖及处方量的微晶纤维素、羧甲淀粉钠加入混匀，最后加入硬脂酸镁混匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.5mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例2帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼，加入5倍量乳糖混合后进行气流粉碎，再向所得混合粉末中加入5倍乳糖混合均匀，然后再将剩余乳糖及处方量的微晶纤维素、羧甲淀粉钠加入混匀，最后加入硬脂酸镁混匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.25mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例3帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼，加入5倍量乳糖混合后进行气流粉碎，再向所得混合粉末中加入5倍乳糖混合均匀，然后再将剩余乳糖及处方量的微晶纤维素、羧甲淀粉钠加入混匀，最后加入硬脂酸镁混匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.75mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例4帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼，加入5倍量乳糖混合后进行气流粉碎，再向所得混合粉末中加入5倍乳糖混合均匀，然后再将剩余乳糖及处方量的微晶纤维素、羧甲淀粉钠加入混匀，最后加入硬脂酸镁混匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.5mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例5帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼，加入5倍量乳糖混合后进行气流粉碎，再向所得混合粉末中加入5倍乳糖混合均匀，然后再将剩余乳糖及处方量的微晶纤维素、羧甲淀粉钠加入混匀，最后加入硬脂酸镁混匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.5mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例6帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼，加入5倍量乳糖混合后进行气流粉碎，再向所得混合粉末中加入5倍乳糖混合均匀，然后再将剩余乳糖及处方量的交联羧甲基纤维素钠加入混匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.75mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例7帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼、甘露醇、蔗糖、乙醇酸淀粉钠、微粉硅胶，混合均匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.5mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例8帕洛诺司琼硬胶囊的制备
取处方量盐酸帕洛诺司琼、葡萄糖、糊精、交联聚维酮、硬脂酸钙，混合均匀。对所得粉末于10个不同位置取样，称取各取样点粉末适量(相当于0.5mg帕洛诺司琼)，检测水分、测定各点百分含量。据中间体含量检测结果进行胶囊填充、检验、包装，即得。
实施例9帕洛诺司琼硬胶囊的加速稳定性测试
依据《原料药与药物制剂稳定性试验指导原则》(中国药典2005版二部附录ⅪⅩC)，考察盐酸帕洛诺司琼胶囊在加速试验(40℃±2℃、RH75％±5％)条件下的稳定性。
以市售包装形式(铝塑包装)将实施例1制备的三批样品置于温度40℃±2℃，相对湿度75％±5％的恒温恒湿箱中及避光条件下进行加速试验，并分别于第1、2、3、6月取样检测，检测结果与0月的初始结果进行比较，结果见表1。
表1：
实施例10帕洛诺司琼硬胶囊剂生物利用度测试
依据《药物制剂人体生物利用度和生物等效性试验指导原则》(中国药典2005版二部附录XIX B)，进行帕洛诺司琼硬胶囊剂生物利用度测试。
选择12名健康受试者，男女各半，对实施例1制备的盐酸帕洛诺司琼硬胶囊剂(0.5mg)进行口服，与单剂量静脉注射盐酸帕洛诺司琼注射液0.5mg的比较，测定口服盐酸帕洛诺司琼胶囊的绝对生物利用度。
试验结果：口服盐酸帕洛诺司琼胶囊的绝对生物利用度(F为109.9±26.1％)与静脉注射相当。
实施例11溶出试验对比
取实施例1制备的盐酸帕洛诺司琼硬胶囊剂，参照专利申请WO2010/077669中的溶出度试验条件，以0.01M盐酸溶液500ml为溶出介质，转速为每分钟75转，依法操作，并于第15、30、45、60分钟取溶出液适量(各时间点的溶出液取样体积均为3ml，并及时在溶出杯中补充相同体积、相同温度的溶出介质)，滤过，取续滤液作为供试品溶液；另精密称取盐酸帕洛诺司琼对照品适量，用0.01M盐酸溶液溶解并稀释制成每1ml中约含帕洛诺司琼1ug的溶液，摇匀，作为对照品溶液。按外标法计算每粒胶囊于各时间点的药物累积溶出量。检测结果见下表2。
表2：
Claims (3)
1.一种帕洛诺司琼的固体药物组合物，其由帕洛诺司琼或其可药用盐、稀释剂、崩解剂和润滑剂组成，所述帕洛诺司琼可药用盐为帕洛诺司琼盐酸盐，稀释剂为乳糖、微晶纤维素的混合物，稀释剂与帕洛诺司琼或其可药用盐(以帕洛诺司琼计)的重量比为190:1，崩解剂为羧甲基淀粉纳，崩解剂与帕洛诺司琼或其可药用盐(以帕洛诺司琼计)的重量比为10:1，润滑剂为硬脂酸镁，润滑剂与帕洛诺司琼或其可药用盐(以帕洛诺司琼计)的重量比为1:1，所述固体药物组合物为硬胶囊。
2.权利要求1所述的药物组合物的制备方法，包括将帕洛诺司琼或其可药用盐、稀释剂、崩解剂和润滑剂均匀混合，然后制成硬胶囊。
3.权利要求1所述的药物组合物在制备预防和治疗呕吐的药物中的应用。
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