CN113577034A - 一种兽用促黄体素释放激素a3冻干粉针剂及制备方法 - Google Patents
一种兽用促黄体素释放激素a3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促黄体素释放激素A3冻干粉针剂的制备方法,包括如下步骤:将乳糖加入到注射用水中,再加入L‑精氨酸、促黄体素释放激素A3、磷酸二氢钠、表面活性剂,溶解后用注射用水定容,调节pH后经过大孔吸附树脂处理,再经过滤除菌,配制成药液;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;然后调节真空度至10Pa以下,温度再升高至0℃后,调节真空度至20Pa,保温8h;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;该方法缩短了冻干时间,生产成本较低,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,特别涉及一种兽用促黄体素释放激素A3冻干粉针剂及制备方法。
背景技术
促黄体素释放激素A3,其化学名称为5’-氧代腩氨酰-L-组氨酰-L-色氨酰-L-丝氨酰-L-酪氨酰-甘氨酰-L-亮氨酰-L-精氨酰-L-脯氨酰-甘氨酰胺,分子式为C55H75N17O13;分子量为1182.33。
促黄体素释放激素A3属于激素类药,其为丘脑下部释放的促黄体素释放激素的类似物,兼具有促黄体素和促卵泡素作用,能促使动物腺垂体释放促黄体素(LH)和促卵泡素(FSH),使血浆中LH浓度明显升高(FSH浓度轻度升高),促使卵巢的卵泡成熟而排卵。对雄性动物,促黄体素释放激素A3可促进精子形成。促黄体素释放激素A3不但可使垂体合成的激素立即释放,也能够刺激激素合成。这种激素类药可以用于治疗奶牛排卵迟滞、卵巢静止、持久黄体、卵巢囊肿及早期妊娠诊断,亦可用于鱼类诱发排卵。
对于促黄体素释放激素A3冻干粉而言,现有的制备方法存在一定的缺点;比如,冻干时间较长,使得促黄体素释放激素A3处于非干燥状态的时间长,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促黄体素释放激素的损伤;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,有一部分促黄体素释放激素会被活性炭吸附,造成最终的冻干粉中有效成分含量降低。
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促黄体素释放激素A3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,制得的兽用促黄体素释放激素A3冻干粉针剂的有效成分含量较高,产品质量稳定。
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:
一种兽用促黄体素释放激素A3冻干粉针剂的制备方法,包括如下步骤:
(1)将乳糖加入到注射用水中,再加入L-精氨酸、促黄体素释放激素A3、磷酸二氢钠、表面活性剂,溶解后用注射用水定容,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5;然后经过大孔吸附树脂处理,再经过0.22μm灭菌过滤器过滤除菌,配制成药液;
(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,促黄体素释放激素A3、L-精氨酸、磷酸二氢钠、乳糖、表面活性剂的质量比为0.025:0.2~0.4:1~2:10~20:0.1~0.5。
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,该处理过程为: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,所述表面活性剂为吐温80。
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促黄体素释放激素A3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:
本发明的促黄体素释放激素A3冻干粉针剂的制备方法,采用乳糖作为冻干赋形剂,既可以使促黄体素释放激素A3在冻干过程中容易成形,又可保证产品的质量;
本发明的制备方法中加入了L-精氨酸,可以对促黄体素释放激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促黄体素释放激素等有效成分,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;
本发明的制备方法中加入了表面活性剂,可以防止原料在药液中的聚集,提高药液中成分的均匀性;
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,以使促黄体素释放激素A3尽快脱离非干燥状态,从而提高了兽用促黄体素释放激素A3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
注射用水补加至80L;
(1)将800g乳糖加入到10L注射用水中,搅拌至完全溶解,得到乳糖溶液,再将16gL-精氨酸、2g促黄体素释放激素A3、80g磷酸二氢钠、8g表面活性剂吐温80,用1L水溶解后,倒入乳糖溶液中,再用注射用水定容至80L,再以350rpm的转速搅拌30min;用pH调节剂调节pH至5.8;然后经过大孔吸附树脂处理,再经过0.22μm灭菌过滤器过滤除菌,配制成药液;
(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1所示。
表1
实施例2
注射用水补加至80L;
(1)将1200g乳糖加入到10L注射用水中,搅拌至完全溶解,得到乳糖溶液,再将24gL-精氨酸、2g促黄体素释放激素A3、120g磷酸二氢钠、15g吐温80,用1L水溶解后,倒入乳糖溶液中,再用注射用水定容至80L,再以350rpm的转速搅拌30min;用pH调节剂调节pH至5.8;然后经过大孔吸附树脂处理,再经过0.22μm灭菌过滤器过滤除菌,配制成药液;
(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2所示。
表2
实施例3
注射用水补加至80L;
(1)将1600g乳糖加入到10L注射用水中,搅拌至完全溶解,得到乳糖溶液,再将32gL-精氨酸、2g促黄体素释放激素A3、160g磷酸二氢钠、40g吐温80,用1L水溶解后,倒入乳糖溶液中,再用注射用水定容至80L,再以350rpm的转速搅拌30min;用pH调节剂调节pH至5.9;然后经过大孔吸附树脂处理,再经过0.22μm灭菌过滤器过滤除菌,配制成药液;
(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4h,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
以下为稳定性加速试验
按照实施例1、2及3的方法各制备1批促黄体素释放激素A3冻干粉针剂,进行稳定性加速试验,即将制成的促黄体素释放激素A3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促黄体素释放激素A3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1.87%、1.51%、1.75%,平均为(1.71±0.01)%,RSD=0.57,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 (7)
1.一种兽用促黄体素释放激素A3冻干粉针剂的制备方法,其特征在于,包括如下步骤:
(1)将乳糖加入到注射用水中,再加入L-精氨酸、促黄体素释放激素A3、磷酸二氢钠、表面活性剂,溶解后用注射用水定容,再以350rpm的转速搅拌30min;用pH调节剂调节pH至4.5~6.5;然后经过大孔吸附树脂处理,再经过0.22μm灭菌过滤器过滤除菌,配制成药液;
(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。
2.根据权利要求1所述的一种兽用促黄体素释放激素A3冻干粉针剂的制备方法,其特征在于,步骤(1)中,促黄体素释放激素A3、L-精氨酸、磷酸二氢钠、乳糖、表面活性剂的质量比为0.025:0.2~0.4:1~2:10~20:0.1~0.5。
3.根据权利要求1所述的一种兽用促黄体素释放激素A3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。
4.根据权利要求1所述的一种兽用促黄体素释放激素A3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。
5.根据权利要求1所述的一种兽用促黄体素释放激素A3冻干粉针剂的制备方法,其特征在于,所述表面活性剂为吐温80。
6.根据权利要求1所述的一种兽用促黄体素释放激素A3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。
7.一种兽用促黄体素释放激素A3冻干粉针剂,其特征在于,其是利用权利要求1-6任一项所述的制备方法制得。
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