CN105535941B - 鲑降钙素制剂工艺 - Google Patents
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/23—Calcitonins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
本发明公开了一种生产鲑降钙素制剂的方法,该方法包括:(1)配制溶媒:a.配制5%的葡萄糖溶液;b.配制氢氧化钠溶液和醋酸溶液;c.获得溶媒;(2)冲洗管路;(3)用配制的溶媒将称量的鲑降钙素溶解,搅拌均匀,除菌过滤后获得药液;(4)保持药液温度和环境温度在12‑20℃;(5)灌封。
Description
技术领域
本发明涉及一种药物的制剂工艺。
背景技术
鲑降钙素在治疗骨质疏松领域有着举足轻重的地位。而且鲑降钙素活性高,临床使用浓度低,在微克级,其液体制剂生产中,均匀性矛盾比较突出,实现所述鲑降钙素制剂的均匀性对于其生产有比较突出的实际意义。
据统计,目前全世界大约2亿人患骨质疏松症,其跃居各种常见病的第7位,预计到2050年,世界人口将增加到120亿,老年人口将增加到14.4亿,占总数的14.7%。骨质疏松症及与之相随的骨折越来越引起社会的关注。尤其是绝境后骨质疏松症的妇女,其骨量下降远大于同龄男性,症状比男性更重,发展更快,骨痛表现更明显。世界上已有许多治疗上的研究,尤其是70年代就发现了降钙素的临床治疗作用。
1991年3月,瑞士诺华公司的鲑降钙素获得了美国FDA的批准,以商品名Miacalcin上市。该品的效用高于人降钙素20倍,抑制破骨细胞的活性较天然降钙素强50倍;多年的临床应用表明,该品治疗妇女停经后的骨质疏松疗效较好,不良反应轻。1994年,瑞士诺华公司的“密钙息”在我国获得注册,其他在我国获得注册的鲑降钙素还有意大利Lisapharma公司、丹麦Peptech(Europe)公司的产品。
鲑降钙素(Salcalcitonin)是由32个氨基酸组成的多肽类物质,是一类具有高度活性的降钙素。它是显著地降低高周转性骨病的骨钙丢失,诸如骨质疏松症、变形性骨病(Paget氏病)、痛性神经营养不良症(Sudeck氏病)和恶性骨质溶解症,它对停经后骨质疏松症的躯干骨作用比四肢骨更显著和对高周转性骨病更显著。它能抑制破骨细胞活性,同时刺激成骨细胞形成和活性。鲑降钙素也能抑制溶骨作用,从而使病理性长高的血钙浓度降低以及通过减少肾小管再吸收而增加尿钙、磷和血钠的排泄;然而血清钙不会降至正常范围以下。降钙素抑制胃和胰腺的分泌活动,但并不影响胃肠蠕动。临床试验证明本品对某些痛性骨病的病人具有止痛作用。所有的降钙素结构上相似,具有单链、排列不同的32个氨基酸。氨基酸的排列顺序取决于物种。鲑降钙素对它的受体结合部位具有很高的亲和力(它的受体结合部位在中枢神经系统的某些区域也已经被证明),具有十分良好的临床效果并且比合成的哺乳类(包括人)的降钙素,作用持续的时间更长。
目前,鲑降钙素临床上已经在使用的剂型有注射剂、鼻用喷雾剂、皮下埋植剂。其中,注射剂有50单位(8.3微克/ml)、100单位(16.7微克/ml)、喷鼻剂有0.2毫克/ml、0.33毫克/ml,药液浓度低,而且由于鲑降钙素的非特异性吸附,引起鲑降钙素液体制剂生产过程中,药液均匀性、产品含量均匀度的矛盾相当突出。这对临床使用也带来相当风险,浓度高的会引起副反应,浓度低了影响疗效。
发明概述
本发明涉及一种鲑降钙素注射剂的生产方法,包括:
(1)配制溶媒
a.配制5%的葡萄糖溶液:将称量的无水葡萄糖用20%配制体积的注射用水溶解,加入质量比千分之一的针用活性炭,加热至沸腾10分钟,冷却到35℃,除掉活性炭,补加不高于25℃的注射用水至配制总体积,搅拌均匀,即得;
b.配制氢氧化钠溶液和醋酸溶液:用占配制总体积约15-25%的5%葡萄糖溶液溶解称量的氢氧化钠,将量取的冰醋酸加入到剩余的占配制总体积约75-85%的葡萄糖溶液,得到醋酸溶液;
c.获得溶媒:将氢氧化钠溶液和醋酸溶液混合,搅拌均匀,即得,pH为3-5;
(2)冲洗管路:用溶媒充分润洗药液管道容器;
(3)用配制的溶媒将称量的鲑降钙素溶解,搅拌均匀,除菌过滤后获得药液;
(4)保持药液温度和环境温度在12-20℃;
(5)灌封:在无菌条件下进行灌装封口。
根据本发明的一种优选的实施方式,在上述的生产方法的(1)(b)所述的配制氢氧化钠溶液和醋酸溶液中,所用的5%葡萄糖溶液的比例分别为20-25%和75-80%。
根据本发明的一种优选的实施方式,在上述的生产方法的(1)(c)中获得溶媒pH值为4.5±0.3。
根据本发明的一种优选的实施方式,在上述的生产方法的(1)(c)中获得溶媒pH值为3.9±0.1。
根据本发明的一种优选的实施方式,在上述的生产方法中药液和环境温度为18-20℃。
根据本发明的一种优选的实施方式,在上述的生产方法中药液和环境温度为12至低于18℃。
根据本发明的一种优选的实施方式,在上述的生产方法的(1)中(c)中获得溶媒pH值为4.5±0.3,且药液温度和环境温度18-20℃。
根据本发明的一种优选的实施方式,在上述的生产方法的(1)中(c)中获得溶媒pH值为3.9±0.1,且药液温度和环境温度12℃至低于18℃。
令人惊讶地发现本发明的上述方法获得了相比现有技术高的制剂均匀性。
发明详述
在此描述本发明的具体实施方式。然而,这仅仅是为了示例性的目的且只提供了内容以进一步理解本发明。本发明并不受限于以下描述的内容,但包括由本领域技术人员所理解所有替换、改进和等价物,落在所附权利要求的主旨和范围内。
本发明人为了解决上述鲑降钙素制剂生产过程中出现的药液均匀性、产品含量均匀度较差,不稳定的问题,进行了以下研究。
研究过程:
目的:找出影响药液均匀性的因素,主要是对鲑降钙素的吸附因素,然后采取有针对性的措施来保证鲑降钙素制剂生产的均匀性。
1考察不同容器表面对鲑降钙素溶液中主药的吸附影响。
选不同容器:材质相同、内表面光洁度有差异的不锈钢容器,选用的是316L材质的不锈钢小桶,2个,一个光洁度≤0.28,一个≥0.45;两种材质的安瓿瓶,一种是1ml中性硼硅的安瓿瓶,一种是1ml低硼硅安瓿瓶。
药液浓度:配制10微克/毫升、0.25毫克/毫升的水溶液,分别加入到以上容器中,在25℃下存放,每30分钟取样检测浓度。
结论:不锈钢容器对降钙素吸附比较大,而且随着药液浓度的增加而吸附量也增加,吸附平衡时间在1-1.5小时,光洁度≥0.45的拉丝不锈钢小桶,对10微克/毫升的药液最大吸附可达60-70%,对0.25毫克/毫升的药液最大吸附可达5-10%;光洁度≤0.28的拉丝不锈钢小桶,对10微克/毫升的药液最大吸附可达10-15%,对0.25毫克/毫升的药液最大吸附可达1%左右;不同材质的玻璃对鲑降钙素吸附的差异不明显,中性硼硅、低硼硅玻璃安瓿对10微克/毫升的药液最大吸附可达5-8%左右,对0.25毫克/毫升的药液无明显吸附。
2考察不同温度对鲑降钙素吸附的影响
选择对降钙素吸附较大的容器:316L不锈钢小桶3个,药液浓度(水溶液)选在10微克/毫升,分别存放在三个小桶中,将三个小桶分别置于2-8℃、20-25℃、30-35℃环境下静置1.5小时,取样测量;然后将30-35℃环境下小桶换到2-8摄氏度静置1.5小时,取样测量。
结论:温度对鲑降钙素的吸附影响成正相关,温度越高,越有利于鲑降钙素的吸附,当温度下降后,已经吸附的鲑降钙素还能解吸。
3药液不同pH对鲑降钙素吸附的影响
药液浓度选择10微克/毫升,分别用pH 3.4的醋酸盐缓冲液(0.1M的醋酸和醋酸钠)、pH 4.3的醋酸盐缓冲液(0.04M的醋酸和0.02M醋酸钠)、pH 7.4的磷酸盐缓冲液(0.067M的磷酸二氢钾和磷酸二钠)、pH 9.3的碳酸盐缓冲液(1.04M的碳酸钠和碳酸氢钠)来配制药液,分别盛放于316L不锈钢小桶中,在25℃下静置1.5小时,分别取样检测。
结论:中性偏酸pH能抑制鲑降钙素的吸附,pH4.3条件下,吸附最小;中性偏碱条件下,吸附现象明显。
4考察添加表面活性剂对鲑降钙素吸附的抑制作用
选用非离子表面活性剂Pluronic F68和Tween 80
结论:0.5%的浓度和0.05%的浓度的Pluronic F68和Tween 80均能有效抑制鲑降钙素的吸附,但0.5%的浓度比0.05%的浓度显示更强的抑制作用,当浓度下降到0.005%时,几乎看不出有明显的吸附抑制作用。
下表为关于上述因素对于鲑降钙素的吸附的对比试验影响结果
以下操作的实施例提供了用于进一步理解本发明的内容。本发明并不受限于以下描述的实施方式,但包括由本领域技术人员所理解的所有替换,改进,和等价物,落在所附权利要求的主旨和范围内本发明。
实施例
实施例1
本发明人筛选工艺处方:
工艺过程:
(1)配制溶媒
a.配制5%的葡萄糖溶液:将称量的50.05g的无水葡萄糖用占配制总体积1100ml的20%的配制体积的注射用水溶解,加入质量比为千分之一的针用活性炭,加热至沸腾10分钟,冷却到35℃,除掉活性炭,补加不高于25℃的注射用水至配制总体积1100ml,搅拌均匀,即得;
b.配制氢氧化钠溶液和醋酸溶液:用占配制总体积约15-25%的5%葡萄糖溶液溶解称量的0.0823g氢氧化钠,将量取的0.55ml冰醋酸加入到剩余的占配制总体积约75-85%的葡萄糖溶液,得到醋酸溶液;
c.获得溶媒:将氢氧化钠溶液和醋酸溶液混合,搅拌均匀,即得,pH在3-5;
(2)冲洗管路:用溶媒充分润洗药液管道容器;
(3)用配制的溶媒将称量的鲑降钙素溶解,搅拌均匀,除菌过滤后获得药液;
(4)保持药液温度和环境温度在12-20℃;
(5)灌封:在无菌条件下进行灌装封口。
实施例2
发明人对比了现有技术与采用本法明的方法而制备的鲑降钙素制剂的均匀性,结果如下。
其中,所制成的鲑降钙素制剂中的含量指标通过中华人民共和国药典2015版中所记载的标准方法测定。
结论:通过缓冲对精细控制本发明的工艺方法中的条件,能够很好地解决鲑降钙素小容量注射液的产品均匀性不佳问题。
Claims (2)
1.一种生产鲑降钙素注射剂的方法,包括:
(1)配制溶媒
a.配制5%的葡萄糖溶液:将称量的无水葡萄糖用20%配制体积的注射用水溶解,加入质量比为千分之一的针用活性炭,加热至沸腾10分钟,冷却到35℃,除掉活性炭,补加不高于25℃的注射用水至配制总体积,搅拌均匀,即得;
b.配制氢氧化钠溶液和醋酸溶液:用占配制总体积约15-25%的5%葡萄糖溶液溶解称量的氢氧化钠,将量取的冰醋酸加入到剩余的占配制总体积约75-85%的葡萄糖溶液,得到醋酸溶液;
c.获得溶媒:将氢氧化钠溶液和醋酸溶液混合,搅拌均匀,即得,pH为3.9;
(2)冲洗管路:用溶媒充分润洗药液管道容器;
(3)用配制的溶媒将称量的鲑降钙素溶解,搅拌均匀,除菌过滤后获得药液;
(4)保持药液温度和环境温度在12℃至低于18℃;
(5)灌封:在无菌条件下进行灌装封口。
2.权利要求1所述的生产方法,其中(1)中(b)所述的配制氢氧化钠溶液和醋酸溶液中,所用的5%葡萄糖溶液的比例分别为配制总体积的20-25%和75-80%。
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