CN113679677A - 一种兽用血促性素冻干粉针剂及制备方法 - Google Patents
一种兽用血促性素冻干粉针剂及制备方法 Download PDFInfo
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Abstract
本发明公开了一种兽用血促性素冻干粉针剂的制备方法,包括如下步骤:向注射用水中加入血促性素、甘露醇、海藻糖、磷酸二氢钠、聚山梨酯80,溶解后经过大孔吸附树脂处理,加入明胶液和凝聚剂,搅拌30min;调节pH,加入生物交联剂,继续搅拌,再经过滤除菌,配制成微囊药液;预先将冻干机的冷凝器温度降至‑45℃以下;药液灌装入安瓿瓶中,进料至冻干机;板层温度降至‑40℃以下,冷冻2h;调节真空度至10Pa以下,温度升高至0℃后,再调节真空度至20Pa,保温8h;温度再升高至35℃,保温3‑5h,得到兽用血促性素冻干粉针剂;该方法缩短了冻干时间,生产成本低,制得的冻干粉针剂的有效成分含量较高,产品质量稳定。
Description
技术领域
本发明属于兽药技术领域,特别涉及一种兽用血促性素冻干粉针剂及制备方法。
背景技术
孕马血清促性腺激素,即PMSG(Pregnant Mare Serum Gonadotropin),也称为马绒毛膜促性腺激素。它是在怀孕母马血清中发现的一种激素,并已知在妊娠马属动物(驴、斑马等)都有产生,所以有人称为马属动物绒毛膜促性腺激素(eCG)。
PMSG具有类似FSH和LH的双重活性,但以FSH的作用为主,因此有着明显的促卵泡发育的作用,同时有一定的促排卵和黄体形成的功能。此外,其对雄性动物还具有促使精细管发育和性细胞分化的功能。
PMSG是一种经济实用的促性腺激素,在生产上常用以代替较昂贵的FS H而广泛应用于动物的诱发发情、超数排卵或增加排卵率(如提高双羔率),对卵巢发育不全或雄性生精能力衰退等也都可起到一定疗效。
血促性素冻干粉针剂(Gonadorelin for Injection),为血促性素与适宜冻干保护剂形成的无菌冻干制剂,为白色或类白色的冻干块状或粉状物,通用名称为注射用血促性素。
对于血促性素冻干粉针剂而言,现有的制备方法存在一定的缺点;比如,冻干时间较长,使得血促性素处于非干燥状态的时间长,进而使得产品质量不稳定,而且制备过程的能耗大,生产成本高;制备过程容易造成对血促性素的损伤;此外,现有的制备方法一般利用活性炭对配制的药液进行吸附,以进行杂质去除和脱色;在吸附过程中,有一部分血促性素会被活性炭吸附,造成最终的冻干粉中有效成分含量降低。此外,现有的制备方法所生产的血促性素冻干粉产品质量不稳定,不易于储存,且在生产和储存过程中容易出现药物微环境水分含量增加现象,从而而影响药物稳定性。
发明内容
为解决上述技术问题,本发明的目的在于提供一种兽用血促性素冻干粉针剂及制备方法,该制备方法缩短了冻干时间,生产成本较低,制得的兽用血促性素冻干粉针剂的有效成分含量较高,产品质量稳定,易于储存。
为实现上述技术目的,达到上述技术效果,本发明通过以下技术方案实现:
一种兽用血促性素冻干粉针剂的制备方法,包括如下步骤:
(1)向注射用水中加入血促性素、甘露醇、海藻糖、磷酸二氢钠、聚山梨酯80,溶解后经过大孔吸附树脂处理,加入明胶液和凝聚剂,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5,加入生物交联剂,继续搅拌,再经过0.22μm灭菌过滤器过滤除菌,配制成微囊药液;
(2)预先将冻干机的冷凝器温度降至-45℃以下;微囊药液在氮气保护下灌装入安瓿瓶中,进料至冻干机;
(3)在lh内降低板层温度至-40℃以下,冷冻2h;然后调节冻干机的真空度至10Pa以下,在lh内将板层温度升高至0℃,然后调节真空度至20Pa,保温8h;
(4)在lh内将板层温度升高至35℃,保温3-5h,得到该兽用促黄体素释放激素A3冻干粉针剂;其中,保温的前2小时,真空度调节为30Pa。
进一步的,步骤(1)中,每10L注射用水中加入1000单位的血促性素。
进一步的,海藻糖、磷酸二氢钠、甘露醇、聚山梨酯80、明胶液、凝聚剂、生物交联剂的重量比为0.2~0.4:1~2:10~20:0.1~0.2:0.2~0.6:0.1~0.2:0.025~0.05。
进一步的,所述PH调节剂为氢氧化钠溶液或/和乙酸溶液。
进一步的,所述制备方法还包括安瓿瓶的处理过程,处理过程为:先将安瓿瓶瓶经注射用水经超声波清洗机器清洗,再在310~330℃温度下进行干燥灭菌。
进一步的,所述凝聚剂为浓度为60%的硫酸钠溶液。
进一步的,所述生物交联剂为京尼平。
进一步的,明胶液的浓度为4%。
进一步的,所述注射用水的温度为30℃以下。
本发明进一步提供了一种兽用血促性素冻干粉针剂,其是利用上述制备方法制得。
本发明的有益效果是:
本发明的兽用血促性素冻干粉针剂的制备方法,采用甘露醇作为冻干赋形剂,可以使血促性素在冻干过程中容易成形,又可保证产品的质量;本发明还加入了聚山梨酯80,聚山梨酯80可以抑制甘露醇的结晶,使甘露醇保持无定型状态,防止在生产和储存过程中药物基质微环境的水分分布发生变化,避免水分分布变化对药物稳定性的影响。
本发明的制备方法中加入了海藻糖,可以对血促性素的氨基酸序列进行保护,防止其在制备过程中受到破坏,保证冻干粉产品质量;
本发明在配制药液的过程中加入了磷酸二氢钠,实现pH调节,可使药液的pH值与产品冻干后再复溶后的pH值一致,提高产品质量的稳定性;
本发明将制备的药液经过大孔吸附树脂处理,树脂可以吸附药液中的有机物杂质、有色杂质等,但不会吸附药液中的血促性素等有效成分,从而不仅可以保证杂质的有效去除,而且不会产生有效成分被吸附而使得冻干粉产品中有效成分含量降低的问题;
本发明在灌装过程中通过氮气保护尽可能保证药液中的物料不会被氧化,避免产生成分变质;
本发明中加入明胶液、凝聚剂和生物交联剂,在凝聚剂和生物交联剂的作用下,明胶交联固化成囊,包裹血促性素及其他成分,形成微囊,然后通过冻干工艺将微囊冻干;本发明利用明胶和生物交联剂将血促性素冻干粉制成微囊粉,能够有效提高冻干粉的稳定性,易于长期储存;
本发明对冻干工艺条件进行了合理设计,先在-40℃以下冷冻2h,然后调节冻干真空度至10Pa以下,并在该真空度下使温度升高至0℃,再调节真空度至20Pa,保温8h,最后升高至35℃,保温3-5h,其中的前两小时中,真空度调节为30Pa;如此,本发明通过设计合理的冻干温度和真空度,提高了冻干速度,可以使药液快速冻结至共晶点以下,缩短了冻干时间,以使血促性素尽快脱离非干燥状态,从而提高了血促性素冻干粉针剂的质量稳定性。
具体实施方式
下面对本发明的较佳实施例进行详细阐述,以使本发明的优点和特征能更易于被本领域技术人员理解,从而对本发明的保护范围做出更为清楚明确的界定。
实施例1
其中,明胶液的浓度为4%,凝聚剂为浓度为60%的硫酸钠溶液。
(1)向注射用水中加入8000单位血促性素、800g甘露醇、16g海藻糖、80g磷酸二氢钠、8g聚山梨酯80,溶解后经过大孔吸附树脂处理,加入16g明胶液和16g凝聚剂,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5,加入2g京尼平,继续搅拌,再经过0.22μm灭菌过滤器过滤除菌,配制成微囊药液;
(2)预先将冻干机的冷凝器温度降至-45℃以下;药液在氮气保护下灌装入安瓿瓶中,进料至冻干机;
(3)在lh内降低板层温度至-40℃以下,冷冻2h;然后调节冻干机的真空度至10Pa以下,在lh内将板层温度升高至0℃,然后调节真空度至20Pa,保温8h;
(4)在lh内将板层温度升高至35℃,保温3h,得到该兽用血促性素冻干粉针剂;其中,保温的前2小时,真空度调节为30Pa。
冻干结束后,将安瓿瓶进行液压加塞,轧盖,包装。
产品全项检验结果如表1所示。
表1
实施例2
其中,明胶液的浓度为4%,凝聚剂为浓度为60%的硫酸钠溶液。
(1)向注射用水中加入8000单位血促性素、1200g甘露醇、24g海藻糖、120g磷酸二氢钠、12g聚山梨酯80,溶解后经过大孔吸附树脂处理,加入24g明胶液和8g凝聚剂,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5,加入3g京尼平,继续搅拌,再经过0.22μm灭菌过滤器过滤除菌,配制成微囊药液;
(2)预先将冻干机的冷凝器温度降至-45℃以下;药液在氮气保护下灌装入安瓿瓶中,进料至冻干机;
(3)在lh内降低板层温度至-40℃以下,冷冻2h;然后调节冻干机的真空度至10Pa以下,在lh内将板层温度升高至0℃,然后调节真空度至20Pa,保温8h;
(4)在lh内将板层温度升高至35℃,保温3h,得到该兽用血促性素冻干粉针剂;其中,保温的前2小时,真空度调节为30Pa。
冻干结束后,将安瓿瓶进行液压加塞,轧盖,包装。
产品全项检验结果如表2所示。
表2
实施例3
其中,明胶液的浓度为4%,凝聚剂为浓度为60%的硫酸钠溶液。
(1)向80L注射用水中加入8000单位血促性素、1600g甘露醇、32g海藻糖、160g磷酸二氢钠、16g聚山梨酯80,溶解后经过大孔吸附树脂处理,加入48g明胶液和12g凝聚剂,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5,加入4g京尼平,继续搅拌,再经过0.22μm灭菌过滤器过滤除菌,配制成微囊药液;
(2)预先将冻干机的冷凝器温度降至-45℃以下;药液在氮气保护下灌装入安瓿瓶中,进料至冻干机;
(3)在lh内降低板层温度至-40℃以下,冷冻2h;然后调节冻干机的真空度至10Pa以下,在lh内将板层温度升高至0℃,然后调节真空度至20Pa,保温8h;
(4)在lh内将板层温度升高至35℃,保温3h,得到该兽用促黄体素释放激素A3冻干粉针剂;其中,保温的前2小时,真空度调节为30Pa。
冻干结束后,将安瓿瓶进行液压加塞,轧盖,包装。
产品全项检验结果如表3所示。
表3
以下通过稳定性试验进一步说明本发明。
按照实施例1、2及3的方法各制备1批血促性素冻干粉针剂,进行稳定性加速试验,即将制成的血促性素冻干粉针剂置于40±2℃的恒温箱中,分别于0、1、3、6个月对性状、pH值、含量均匀度、含量四个项目进行考察,按照兽药质量标准2017年版化学药品卷进行检测,结果如表4所示。
表4稳定性加速试验结果
从表4可以看出,各项指标无明显变化,均符合国家药品标准的规定,说明采用本发明的工艺制备的血促性素冻干粉针剂的稳定性较好。并且,第6个月末样品的含量变化分别为1.08%、0.68%、1.02%,平均为(0.91±0.01)%,RSD=0.30,进一步验证了本发明工艺条件的可靠性。
以上所述仅为本发明的实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书内容所作的等效结构或等效流程变换,或直接或间接运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (10)
1.一种兽用血促性素冻干粉针剂的制备方法,其特征在于,包括如下步骤:
(1)向注射用水中加入血促性素、甘露醇、海藻糖、磷酸二氢钠、聚山梨酯80,溶解后经过大孔吸附树脂处理,加入明胶液和凝聚剂,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5,加入生物交联剂,继续搅拌,再经过0.22μm灭菌过滤器过滤除菌,配制成微囊药液;
(2)预先将冻干机的冷凝器温度降至-45℃以下;微囊药液在氮气保护下灌装入安瓿瓶中,进料至冻干机;
(3)在lh内降低板层温度至-40℃以下,冷冻2h;然后调节冻干机的真空度至10Pa以下,在lh内将板层温度升高至0℃,然后调节真空度至20Pa,保温8h;
(4)在lh内将板层温度升高至35℃,保温3-5h,得到该兽用血促性素冻干粉针剂;其中,保温的前2小时,真空度调节为30Pa。
2.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,步骤(1)中,每10L注射用水中加入1000单位的血促性素。
3.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,海藻糖、磷酸二氢钠、甘露醇、聚山梨酯80、明胶液、凝聚剂、生物交联剂的重量比为0.2~0.4:1~2:10~20:0.1~0.2:0.2~0.6:0.1~0.2:0.025~0.05。
4.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,所述PH调节剂为氢氧化钠溶液或/和乙酸溶液。
5.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,所述制备方法还包括安瓿瓶的处理过程,处理过程为:先将安瓿瓶瓶经注射用水经超声波清洗机器清洗,再在310~330℃温度下进行干燥灭菌。
6.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,所述凝聚剂为浓度为60%的硫酸钠溶液。
7.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,所述生物交联剂为京尼平。
8.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,明胶液的浓度为4%。
9.根据权利要求1所述的一种兽用血促性素冻干粉针剂的制备方法,其特征在于,所述注射用水的温度为30℃以下。
10.一种兽用血促性素冻干粉针剂,其特征在于,其是利用权利要求1-9任一项所述的制备方法制得。
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