CN1047076C - 稳定的注射剂及注射剂的稳定方法 - Google Patents
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Abstract
以配合抗光剂为特征的，以(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并__嗪-8-甲酰胺-盐酸盐为有效成分的稳定注射剂及其稳定方法。通过配合选自亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐，1，2-乙二胺、水杨酸或其金属盐、或者苯酚或其衍生物的1种或2种以上抗光剂，可望防止着色。
Description
技术领域
本发明涉及具有强烈选择性血清素-3受体拮抗作用，可用作改善、治疗伴随顺氯氨铂等抗恶性肿瘤剂的给药的恶心、呕吐、食欲不振等的药剂的(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐的稳定注射剂及含有该化合物的注射剂的稳定剂。
背景技术
特开平2-28182号公报公开了具有强烈选择性血清素-3受体拮抗作用，可用作改善、治疗伴随顺氯氨铂等抗恶性肿瘤剂的给药的恶心、呕吐、食欲不振等的药剂的(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐(以下称作本化合物)，还公开了采用锭剂等经口剖和注射剂等非经口剂的药剂形式。
但是已发现本化合物容易遇光分解，特别是在水溶液或悬浊液状态下稳定性差，发生显著着色变化，对于这些液体制剂，通常采用遮光容器盛放而避免光分解。采用该方法固然可以在药品的流通过程或保存中间抑制其光分解，但在临床使用时往往处于易曝光的状态，不难想象，随着场合的不同，很容易经常发生加速着色变化。
因此，本发明的目的是提供抑制光分解、特别是着色变化的稳定的合有(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐的注射剂及其稳定方法。
发明的公开
本发明者为解决上述课题进行了锐意研究，结果完成了本发明。也就是说，本发明涉及以配合抗光剂为特征的以(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐为有效成分的稳定注射剂，以及在以(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐为有效成分的注射剂中配入抗光剂为特征的注射剂稳定方法。
如上述特开平2-28182号公报所述，用于本发明的有效成分化合物(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐可按下列方法制得：优选在脱氧剂存在下，在对反应为惰性的溶剂中，使6-氯-3,4-二氢-4-甲基-3-氧代-2H-1,4-苯并噁嗪-8-甲酸的活性衍生物(酰氯等)与3-氨基奎宁环反应，然后用盐酸酸化。
另外，用于本发明的抗光剂为选自下列化合物的一种或两种以上物质：亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐、1,2-乙二胺、水杨酸或其金属盐、或者是苯酚或其衍生物。其中优选亚硫酸盐，例如包括焦亚硫酸盐、亚硫酸氢盐、例如亚硫酸钠、亚硫酸钾、亚硫酸氢钠、亚硫酸氢钾、焦亚硫酸钠、焦亚硫酸钾等、特别是焦亚硫酸钠(也可使用含此物的亚硫酸氢钠)在抑制着色变化方面效果优异。这些抗光剂的配合量可随抗光剂的种类变化而变，但对1重量份的本发明化合物有效成分约0.001～约5重量份，优选约0.01～约2重量份。
在本发明的稳定注射剂中也可再配合注射用添加剂，例如渗透压调节剂、pH调整剂、防腐剂、麻醉剂等均可作添加剂使用。其中渗透压调节剂可列举氯化钠等电解质、甘氨酸等氨基酸、葡萄糖等糖类和/或甘露糖醇等多元醇，其配比优选以等渗压浓度以下的浓度使用，对于注射剂的总量通常宜为5％重量/体积，用氯化钠时也可为约0.9％重量/体积。另外，pH调节剂优选将最终pH调至约3～约5的物质，可采用盐酸、柠檬酸、乙酸、乳酸等。必要时也可使用氢氧化钠等碱类。
本发明的注射制剂通过将本发明的化合物，抗光剂、渗透压调节剂和pH调节剂等上述添加剂溶于注射用蒸馏水中，过滤，填充到注射剂用容器中，熔封而制得。过滤可在氮气气氛中进行，另外还优选将填充用容器预先用氮气吹洗干净。再则，在将溶液填充到注射用容器中时，优选用氮气置换容器内空气。还有熔封以后，也可加热灭菌。这样得到的注射剂对曝光稳定，特别是表现出抑制着色变化的优异稳定效果。另外还无溶血性，并确认在血清中无结晶析出性，作为注射剂使用方面无问题。作为最终剂型装入例如遮光容器中时，则可望进一步提高稳定效果。
这样得到的本发明的稳定注射剂表现出优异的血清素-3受体拮抗作用，可用于改善治疗将顺氯氨铂等抗恶性肿瘤剂投药给人类等伴随的恶心、呕吐、食欲不振，治疗慢性胃炎、过敏性肠疾病等消化器官疾病。
将本发明的稳定注射剂用于改善或治疗上述疾病时，可经静脉内给药，皮下给药，肌内给药等途径对患者安全给药。给药量一般为每个成年人每天约0.1～约50mg有效成分(游离碱)，优选约1～约30mg。
实施发明的最佳方式
以下用实施例详细说明本发明，但无庸赘言，本发明不受这些实施例的限定。
实施例1
将(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐10g，焦亚硫酸钠0.5g以及预先在250℃加热灭菌30分钟以上的氯化钠18克溶于适量注射用蒸馏水中，调整为总量2000ml。所得溶液在氨气气氛下用膜滤器(孔径0.45μm)过滤，在2ml容积的安瓿瓶中填充2ml，用氮气置换除去空气，熔封后在115℃灭菌30分钟。
实施例2
将(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐5g，L-半胱氨酸2g及氯化钠9g溶于适量注射用蒸馏水中，加入盐酸调至pH4，调节为总量1000ml的溶液。与上述实旋例1一样，将该溶液封入安瓿瓶中，灭菌后得到2ml注射剂。
实施例3
用(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐5g、巯基乙酸钠3g、氯化钠9g以及适量的盐酸和注射用蒸馏水，与上述实施例1同样地配制总量为1000ml的注射剂。将该溶液与上述实施例1一样装入安瓿瓶中，灭菌后得到2ml注射剂。
实施例4
采用(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐5g、1,2-乙二胺5g、氯化钠9g以及适量盐酸和注射用蒸馏水，和上述实施例1一样，制得总量为1000ml的注射剂，然后得到2ml注射剂。
实施例5
和实施例1一样制得2ml注射剂，只是采用抗坏血酸、水杨酸钠和苯酚作为光稳定剂。
下面用实施例说明本发明注射剂的稳定效果。实验用的注射剂为上述实施例1～4的注射用安瓿瓶，比较用注射剂采用以下处方制剂。
比较用处方
采用(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐5g、氯化钠9g及适量注射用蒸馏水，与实施例1一样制得总量为1000ml的溶液，然后得到2ml注射剂。
实验例1
采用在上述实施例1～4以及比较用处方的白色安瓿瓶内注射剂，在室内散光(约700勒克司)下曝光1小时，然后用肉眼观察外观。结果示于表1中。同样在室内散光(约700勒克司)下曝光7小时后，用分光光度计在400nm和503nm下测定吸光度，结果示于表2。
表1
| 样品名 | 室内散光下1小时后的外观 |
| 实施例1得到的注射液实施例2得到的注射液实施例3得到的注射液实施例4得到的注射液比较处方得到的注射液 | 无色透明无色透明无色透明极浅的黄色淡橙黄色 |
表2
| 样品名 | 室内散光下7小时后溶液的吸光度 | |
| 400nm | 503nm | |
| 实施例1得到的注射液实施例2得到的注射液实施例3得到的注射液实施例4得到的注射液比较处方得到的注射液 | 0.000.070.040.230.49 | 0.000.010.000.041.30 |
产业实用性
从上述说明书，特别是实施例和实验例的描述可看出，根据本发明，可提供具有血清素-3拮抗作用，可作为药物的化合物的稳定注射剂以及注射剂的稳定方法。
Claims (10)
1．稳定注射剂，以(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐为有效成分，其特征在于配合了抗光剂。
2．按权利要求1的注射剂，其中抗光剂为选自亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐、1,2-乙二胺、水杨酸或其金属盐或者苯酚或其衍生物的1种或2种以上物质。
3．按权利要求1或2的注射剂，其中抗光剂为选自亚硫酸盐的1种或2种以上物质。
4．按权利要求1、2或3的注射剂，其中亚硫酸盐选自亚硫酸钠、亚硫酸钾、亚硫酸氢钠、亚硫酸氢钾、焦亚硫酸钠、焦亚硫酸钾。
5．按权利要求4的注射剂，其中抗光剂为焦亚硫酸钠。
6．注射剂的稳定方法，其特征在于在含有(±)-6-氯-3,4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1,4-苯并噁嗪-8-甲酰胺-盐酸盐作为有效成分的注射剂中配合抗光剂。
7．按权利要求6的稳定方法，其中抗光剂为选自亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐、1,2-乙二胺、水杨酸或其金属盐或者苯酚或其衍生物的1种或2种以上物质。
8．按权利要求7的稳定方法，其中抗光剂为选自亚硫酸盐的1种或2种以上物质。
9．按权利要求6、7或8的稳定方法，其中亚硫酸盐为选自亚硫酸钠、亚硫酸钾、亚硫酸氢钠、亚硫酸氢钾、焦亚硫酸钠、焦亚硫酸钾。
10．按权利要求9的方法，其中抗光剂为焦亚硫酸钠。
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| US5952387A (en) * | 1995-08-04 | 1999-09-14 | Hokuriku Seiyaku Co., Ltd. | Photostable aqueous solution containing benzyl alcohol derivatives |
| JP2008297277A (ja) * | 2007-06-01 | 2008-12-11 | Taiyo Yakuhin Kogyo Kk | 注射剤の安定化法 |
| CN102164606B (zh) * | 2008-09-30 | 2014-04-16 | 电气化学工业株式会社 | 光稳定化药物组合物 |
| CN103432078B (zh) * | 2013-08-28 | 2015-06-17 | 芦红代 | 盐酸头孢甲肟的药物组合物 |
| US11185509B2 (en) * | 2016-07-29 | 2021-11-30 | Toray Industries, Inc. | Solid preparation having improved light stability |
| CN106943310B (zh) * | 2017-01-25 | 2020-07-17 | 西安科艺诗生物技术有限公司 | 一种提高色素蛋白光稳定性的复合物及应用 |
| CN116158429B (zh) * | 2021-11-25 | 2024-06-18 | 沈阳中化农药化工研发有限公司 | 一种含有联苯类化合物稳定的液体制剂 |
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| US3597456A (en) * | 1969-05-20 | 1971-08-03 | Squibb & Sons Inc | Method for preparing sterile lecithin |
| JPS4819929B1 (zh) * | 1970-05-12 | 1973-06-18 | ||
| JPS51136818A (en) * | 1975-05-20 | 1976-11-26 | Yamanouchi Pharmaceut Co Ltd | Method for preparing stable prostaglandine pharma ceuticals |
| JPS5270014A (en) * | 1975-12-05 | 1977-06-10 | Senju Pharma Co | Stabilization of pyrido*3*22a*phenoxadine compounds |
| JPS58203910A (ja) * | 1982-05-20 | 1983-11-28 | Nikken Kagaku Kk | ドパミン含有点滴静注用剤 |
| JPS60169430A (ja) * | 1984-02-14 | 1985-09-02 | Teijin Ltd | プロスタグランジン類製剤用組成物 |
| JPH0778020B2 (ja) * | 1987-06-10 | 1995-08-23 | 日本化薬株式会社 | 安定な総合ビタミン凍結乾燥製剤 |
| JP2761005B2 (ja) * | 1988-11-02 | 1998-06-04 | エーザイ株式会社 | セファロスポリン含有注射用組成物 |
| NL8901432A (nl) * | 1989-06-06 | 1991-01-02 | Pharmachemie Bv | Bij koelkasttemperatuur stabiele waterige folinaatoplossing, alsmede werkwijze ter bereiding daarvan. |
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| KR100188318B1 (ko) | 1999-06-01 |
| WO1994025032A1 (en) | 1994-11-10 |
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