CN1402636A - 含有zolmitriptan的药用制剂 - Google Patents
含有zolmitriptan的药用制剂 Download PDFInfo
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- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
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- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
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- A61K9/00—Medicinal preparations characterised by special physical form
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
一种用于鼻内给药的5HT1激动剂zolmitriptan的药用制剂。该制剂可用于治疗偏头痛和相关疾病。
Description
本发明涉及新的药用制剂、其制备以及其在疾病治疗中的应用。具体地说，本发明涉及供鼻用药的抗偏头痛药zolmitriptan的药用制剂。
zolmitriptan的化学名称是(S)-4-{{3-[2-(二甲氨基乙基]-1H-吲哚-5-基]甲基]-2-噁唑烷酮。zolmitriptan是一种选择性5HT1受体激动剂。5HT1受体介导血管收缩，因此调节流向颈动脉血管床的血流。5HT1受体激动剂在其中表明颈动脉血管床中有血管收缩的病症的治疗(包括预防)方面是有益的，所述病症例如偏头痛、偏头神经痛和与血管性疾病有关的头痛，在下文中这些统称“偏头痛”。已经开发了zolmitriptan，以2.5mg和5mg的片剂、计划每天摄取最多15mg来急性治疗偏头痛。
虽然zolmitriptan是一种对偏头痛患者相当有益的成功的药物，但持续需要直接治疗偏头痛和预防性治疗偏头痛的替代方法。特别是，患有偏头痛或偏头痛发作的患者需要迅速缓解其痛苦。
zolmitriptan是一类称为triptans的药物中的一个成员，该类药物例如舒马普坦、那拉曲坦和rizatriptan，用于治疗偏头痛。就销售而言，先导药物是舒马普坦，它已经作为口服制剂在市场上出售。也开发了皮下制剂；这种制剂的功效更强(P Tfelt-Hansen，Cephalalgia 1998，第18卷(8)，第532-8页)，并且更为快速地起效，但患者不是那么愿意接受。也开发了鼻内喷雾剂。这比皮下注射剂对于使用者更为友好，但据报道在缓解偏头痛发作症状方面效力较低(C Dahlof，Cephalalgia1998；18(5)：278-282)。此外，许多患者报告在使用该鼻用喷雾剂后有令人不快的苦味。
本发明人寻找一种达到快速缓解而同时保持高功效的zolmitriptan制剂。他们也寻找对于患有偏头痛的各种各样的患者而言给药途径比皮下注射更易被接受的制剂。显然，皮下注射的想法可能阻止了患者采用合适的和必不可少的治疗。此外，本发明人寻找一种方便、有效和可为患者接受但不引起不必要的刺激或副作用的制剂。
USP5466699公开了一类用于治疗和预防偏头痛的化合物。USP5466699公开了，该类化合物可以配制用于经口、舌下、口含、胃肠外(例如皮下、肌内或静脉内)、直肠、局部和鼻内给药，公开了这类可能的制剂的实例，包括鼻内制剂的实例。所述鼻内制剂由活性成分、羟基苯甲酸甲酯(0.2％)、羟基苯甲酸丙酯(0.02％)、柠檬酸盐缓冲液和足够的盐酸(以使得pH为7)组成。
本发明人设计了一种为偏头痛患者提供有效的和改善的快速缓解作用的zolmitriptan鼻内制剂。虽然本发明人不希望受理论的约束，但认为这至少部分是由于直接经粘膜吸收相当比例的通过鼻内途径给予的zolmitriptan所致。
此外，用pH7.0以上的zolrmitriptan鼻内制剂在pH7.4下进行的研究，表明该制剂的稳定性在延长的时间内是不被接受的。
本发明人用pH低于7.0的稳定的zolmitriptan鼻内制剂提供了改善的快速起效。另外，这种制剂可为一般患者群体所接受，并且不引起不必要的刺激或副作用。
因此，本发明人提供适用于鼻内给药的药用制剂，所述药用制剂包含zolmitriptan和一种药学上可接受的载体，其中所述制剂的pH低于7.0。
用于鼻内给药的zolmitriptan制剂一般作为水性制剂制备，并且通常是加有缓冲剂的。合适的缓冲剂包括柠檬酸、磷酸盐例如磷酸氢二钠(例如十二水合物、七水合物、二水合物和无水形式)或磷酸钠以及它们的混合物(例如McIlvaine氏缓冲剂，它为柠檬酸和磷酸氢二钠的混合物)。
在一个具体的方面，zolmitriptan药用制剂的pH低于6.0，例如范围为3.5-5.5，尤其范围为4.5-5.5。在一个具体的方面，所述制剂的pH约为5.0。
除缓冲剂外，所述zolmitriptan制剂还可以含有通常在鼻内制剂中发现的其它成分，诸如抗氧化剂例如焦亚硫酸钠、遮味剂例如甲醇以及甜味剂例如葡萄糖、甘油、糖精和山梨醇。
另一方面，本发明提供zolmitriptan在pH低于7.0、尤其是pH低于6.0、例如范围为3.5-5.5、尤其范围是4.5-5.5、例如约5.0的缓冲液中的水溶液。特别是，本发明提供zolmitriptan在pH低于7.0、尤其是pH低于6.0、例如范围为3.5-5.5、尤其范围是4.5-5.5、例如约5.0的柠檬酸和磷酸盐的缓冲液中的水溶液。
本发明的药用制剂可以与一种或多种用于治疗偏头痛或相关病症的药物共同给予(同时或顺序给予)。
本发明的药用制剂通常将给予人，因此例如将约0.5mg-15mg(例如0.5mg、1.0mg、2.5mg、5.0mg和10mg)的zolmitriptan给予需要此治疗的患者。正如鼻内领域所知，所述制剂的浓度和体积是可以变化的，通常给予50-250μl的体积，例如50μl或100μl(以一剂喷雾剂或以两剂50μl的喷雾剂-一个鼻孔一剂)。所给予的精确剂量取决于本领域已知的各种因素，包括待治疗患者的体重、年龄和性别以及待治疗的具体的偏头痛病症。可以在偏头痛发作开始或发作过程中的任何阶段摄入这样一种单位剂量。可以根据需要摄入这样一种单位剂量，通常为一天摄入1-3次。
通过将zolmitriptan溶于酸性介质、例如柠檬酸水溶液中，由此形成zolmitriptan的柠檬酸盐，并且通过加入合适的试剂例如磷酸盐将pH调至所需数值，可以制备本发明的药用制剂。通常生产最后的经缓冲的溶液，以确保它含有低生物负荷或确保它是无菌的。通常，例如通过使所述溶液通过无菌滤膜(例如0.2μm)，或压热器处理，将所述溶液灭菌。最好是，用氮气吹扫所述溶液，并且在主要的包装中充入氮气，以最大限度地减少降解的可能性。或者，可以使用另一种惰性气体，例如氩气。因此，另一方面，本发明提供一种适用于鼻内给药的无菌药用制剂，所述药用制剂包含zolmitriptan和一种药学上可接受的载体，其中所述制剂的pH低于7.0。
通常将本发明的药用制剂填充到能够将一个单位剂量量的zolmitriptan传递给予需要此治疗的患者的合适的给药装置中。这类给药装置包括那些市售的装置以及英国登记的外观设计2071555中公开的装置。因此，另一方面，本发明提供一种含有zolmitriptan和药学上可接受的载体的鼻内给药装置，其中所述制剂的pH低于7.0。
可以对填充好的鼻内给药装置进行包装，以提供避光保护。因此，在另一个方面，本发明提供一种避光包装(例如箔制药袋)中的含有zolmitriptan和药学上可接受的载体的鼻内给药装置。在一个可供选择的方面，所述装置本身是深色的，以提供避光保护，例如为深蓝色。
因此，在另一个方面，本发明提供用于治疗性治疗人体或动物体的方法中的适用于鼻内给药的药用制剂，所述药用制剂包含zolmitriptan和药学上可接受的载体，其中所述制剂的pH低于7.0。
在又一方面，本发明提供一种对于其中对5HT1受体的激动作用是有益的病症的治疗方法，所述方法包括给予有效量的适用于鼻内给药的药用制剂，所述药用制剂包含zolmitriptan和药学上可接受的载体，其中所述制剂的pH低于7.0。本发明也提供zolmitriptan和药学上可接受的载体在适用于鼻内给药的药用制剂生产方面的应用，所述制剂的pH低于7.0。
用于本发明制剂中的zolmitriptan可以按照WO91/18897和WO97/06162的公开内容制备。实施例1-4
将zolmitriptan溶于柠檬酸水溶液中，加入0.4M十二水合磷酸氢二钠至pH5.0，加入注射用水至所需体积。这样，制备zolmitriptan浓度为5mg/ml、10mg/ml、25mg/ml和50mg/ml的溶液。将该溶液通过除菌级滤膜(0.2μm)过滤，填充到USP/Ph Eur1型玻璃管形瓶(标称喷雾体积为100μl)中，用氯丁基瓶塞封闭所述管形瓶。表1鼻喷雾剂标称强度 0.5mg 1mg 2.5mg 5mg溶液浓度 5mg/ml 10mg/ml 25mg/ml 50mgmlzolmitriptan 0.5 1.0 2.5 5.0柠檬酸，无水USP/Ph Eur 1.11 1.29 1.79 2.60十二水合磷酸氢二钠 适量至pH 适量至pH 适量至pH 适量至pHUSP/Ph Eur* 5.0 5.0 5.0 5.0注射用水USP/Ph Eur 至0.1ml 至0.1ml 至0.1ml 至0.1ml*以用纯水(USP/Ph Eur)稀释的0.4M十二水合磷酸氢二钠溶液加入。
将管形瓶装配到英国登记的外观设计2071555中公开的单位剂量鼻喷雾装置中。该装置包括一个管形瓶支架、一个驱动装置和一个保护盖。已装配的装置可以用来在一次给药中传递0.5mg、1.0mg、2.5mg或5.0mg的单位剂量的zolmitriptan。将已填充的鼻喷雾装置包装到塑料托盘中，并置于纸板盒中，以提供避光保护。实施例5-8
将zolmitriptan溶于柠檬酸水溶液中，加入0.4M十二水合磷酸氢二钠至pH5.0，加入注射用水至所需体积。这样，制备zolmitriptan浓度为5mg/ml、10mg/ml、25mg/ml和50mg/ml的溶液。将溶液过滤并填充到USP/Ph Eur1型玻璃管形瓶(标称喷雾体积为100μl)中，用氯丁基瓶塞封闭所述管形瓶。表1鼻喷雾剂标称强度 0.5mg 1mg 2.5mg 5mg溶液浓度 5mg/ml 10mg/ml 25mg/ml 50mgmlzolmitriptan 0.5 1.0 2.5 5.0柠檬酸、无水USP/PhEur 1.11 1.29 1.79 2.60磷酸氢二钠USP/Ph Eur* 适量至pH 适量至pH 适量至pH 适量至pH
5.0 5.0 5.0 5.0纯水USP/Ph Eur 0.1ml 0.1ml 0.1ml 0.1ml*以用注射用纯水稀释的0.4M磷酸氢二钠(Ph Eur/USP)溶液加入。
将该管形瓶于121℃压热器处理15分钟。然后将该管形瓶装配到英国登记的外观设计2071555中公开的单位剂量鼻喷雾装置中。该装置包括一个管形瓶支架、一个驱动装置和一个保护盖。已装配的装置可以用来在一次给药中传递0.5mg、1.0mg、2.5mg或5.0mg的单位剂量的zolmitriptan。将已填充的鼻喷雾装置包装到塑料托盘中，并置于纸板盒中，以提供避光保护。实施例9
患者除去所述鼻喷雾装置的包装，然后除去保护盖。然后患者将装置的喷嘴插入鼻孔中，驱动所述装置以给予一个剂量。
Claims (14)
1.一种适用于鼻内给药的药用制剂，所述药用制剂包含zolmitriptan和一种药学上可接受的载体，其中所述制剂的pH低于7.0。
2.一种权利要求1的药用制剂，其中所述制剂的pH范围为4.5-5.5。
3.一种权利要求1或权利要求2的药用制剂，其中所述制剂中加有缓冲剂。
4.一种权利要求3的药用制剂，其中所述缓冲剂是柠檬酸和磷酸氢二钠的混合物。
5.一种权利要求1-4中任一项的药用制剂，所述药用制剂是无菌的。
6.一种制备权利要求5中限定的无菌药用制剂的方法，所述方法包括压热器处理。
7.一种对于其中对5HT1受体的激动作用是有益的病症的治疗方法，所述方法包括给予有效量的权利要求1-5中任一项所限定的药用制剂。
8.zolmitriptan在权利要求1-5中任一项所限定的药用制剂的生产中的应用。
9.一种鼻内给药装置，所述装置含有权利要求1-5中任一项所限定的药用制剂。
10.一种鼻内给药装置，所述装置含有权利要求1-5中任一项所限定的药用制剂，所述给药装置被包装时提供避光保护。
11.一种zolmitriptan在pH低于7.0的缓冲液中的水溶液。
12.一种zolmitriptan在pH范围为4.5-5.5的缓冲液中的水溶液。
13.一种zolmitriptan的柠檬酸盐。
14.一种水溶液中的zolmitriptan的柠檬酸盐。
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| CN100341504C (zh) * | 2004-12-01 | 2007-10-10 | 鲁南制药集团股份有限公司 | 佐米曲普坦速释制剂 |
| CN108135916A (zh) * | 2015-06-19 | 2018-06-08 | 翰林科学股份有限公司 | 手性特异性含硼化合物及其在治疗癌症或淀粉样变性中的应用 |
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| US8465468B1 (en) | 2000-06-29 | 2013-06-18 | Becton, Dickinson And Company | Intradermal delivery of substances |
| GB9928578D0 (en) * | 1999-12-03 | 2000-02-02 | Zeneca Ltd | Pharmaceutical formulations |
| SE0102855D0 (sv) * | 2001-08-27 | 2001-08-27 | Astrazeneca Ab | Method of treatment |
| US20050256182A1 (en) * | 2004-05-11 | 2005-11-17 | Sutter Diane E | Formulations of anti-pain agents and methods of using the same |
| WO2005115345A1 (en) * | 2004-05-28 | 2005-12-08 | Imaginot Pty Ltd | Oral therapeutic compound delivery system |
| US8216610B2 (en) | 2004-05-28 | 2012-07-10 | Imaginot Pty Ltd. | Oral paracetamol formulations |
| EP1812428A2 (en) * | 2004-11-19 | 2007-08-01 | Teva Pharmaceutical Industries Ltd | Zolmitriptan crystal forms |
| EP3263117A1 (en) * | 2005-11-28 | 2018-01-03 | Imaginot Pty Ltd. | Oral therapeutic compound delivery system |
| WO2008016678A2 (en) * | 2006-08-01 | 2008-02-07 | Sunesis Pharmaceuticals, Inc. | Pharmaceutical dosage forms for (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid |
| BRPI0715579A2 (pt) * | 2006-10-19 | 2015-05-26 | Auspex Pharmaceuticals Inc | "composto, composição farmacêutica e uso de um composto" |
| KR101517415B1 (ko) * | 2008-05-14 | 2015-05-07 | 에스케이바이오팜 주식회사 | 난용성 항경련제를 함유하는 경비 항경련성 약학 조성물 |
| AU2011316225B2 (en) | 2010-10-15 | 2016-05-19 | Contera Pharma Aps | Combinations of serotonin receptor agonists for treatment of movement disorders |
| JP6121734B2 (ja) * | 2012-02-09 | 2017-04-26 | 久光製薬株式会社 | マイクロニードル用ゾルミトリプタン含有コーティング組成物及びマイクロニードルデバイス |
| HUE037732T2 (hu) | 2012-04-18 | 2018-09-28 | Contera Pharma Aps | A mozgászavarok fejlett kezelésére alkalmas, szájon át szedhetõ gyógyszerészeti készítmény |
| US11554229B2 (en) | 2013-03-26 | 2023-01-17 | OptiNose Inc. | Nasal administration |
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| WO2017122161A1 (en) | 2016-01-15 | 2017-07-20 | Cadila Healthcare Limited | An intranasal composition comprising 5ht1b/1d receptor agonists |
| EP3481385A1 (en) | 2016-07-11 | 2019-05-15 | Contera Pharma APS | Pulsatile drug delivery system for treating morning akinesia |
| WO2019126766A1 (en) * | 2017-12-21 | 2019-06-27 | Taiwan Liposome Co., Ltd. | Sustained-release triptan compositions and method of use the same through subdermal route or the like |
| US20210322343A1 (en) | 2020-04-15 | 2021-10-21 | Farzana Shaheen | Nasally administered pharmaceutical composition for the treatment of epilepsy and related disorders |
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| GB9928578D0 (en) * | 1999-12-03 | 2000-02-02 | Zeneca Ltd | Pharmaceutical formulations |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100341504C (zh) * | 2004-12-01 | 2007-10-10 | 鲁南制药集团股份有限公司 | 佐米曲普坦速释制剂 |
| CN108135916A (zh) * | 2015-06-19 | 2018-06-08 | 翰林科学股份有限公司 | 手性特异性含硼化合物及其在治疗癌症或淀粉样变性中的应用 |
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