CN114191541A - 喷雾冷冻干燥法制备索玛鲁肽微粒 - Google Patents
喷雾冷冻干燥法制备索玛鲁肽微粒 Download PDFInfo
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Abstract
本发明采用喷雾冷冻干燥法制备索玛鲁肽微粒,获得的产品是球型、表面和内部多孔的粉状或颗粒状产品,完全区别于喷雾干燥的中孔的、团聚型的产品和经干燥并粉碎而成的片状、菱状、针状的冷冻干燥产品,产品具有较好的稳定性和复水性,可用于索玛鲁肽口服固体制剂的制备。
Description
技术领域
本发明涉及一种索玛鲁肽微粒的制备方法,尤其是一种基于喷雾冷冻干燥工艺制备索玛鲁肽微粒的方法。
背景技术
索玛鲁肽(Semaglutide),又译为司美鲁肽,是一种新的长效胰高血糖素样肽-1(GLP-1)类似物,每周皮下注射一次,可使II型糖尿病患者血糖水平大幅改善,并且低血糖风险较低。同时,索玛鲁肽还能够通过降低食欲和减少食物摄入量,诱导减肥。此外,索玛鲁肽还能够显著降低II型糖尿病患者重大心血管事件风险。
2017年12月7日FDA批准了诺和诺德公司索玛鲁肽的上市申请。2019年9月,索玛鲁肽口服制剂获FDA批准上市。
索玛鲁肽的分子结构如下:
纯化后的索玛鲁肽溶液通常采用冷冻干燥方法制备得到固体,但是采用冷冻干燥方法需要较长的升华干燥时间,制备的产品性状为疏松块状物,颗粒直径较大、粒度分布范围广、不规则,在口服片剂生产过程中较难操作,同时也影响在体内的溶出和生物利用度,降低了药物的药效。如果采用研磨或粉碎的方法进行样品处理,摩擦所产生的热作用和机械作用会导致部分药物有效成分的降解。喷雾干燥技术最大特征就是蒸发和干燥的表面积非常大,干燥速率可以急剧提高,但需要在高温瞬间干燥药物液滴,所以不适用于处理热敏感性的药物。
喷雾冷冻干燥技术结合了喷雾干燥和冷冻干燥的优点,能够在缩短干燥时间的同时又保持物料的品质要求,制备出低密度、高比表面积的非晶型体颗粒,所需要的干燥时间极短,缩短了真空冷冻干燥的时间,且干燥后的物料为粉末状的固体,原有的生物、化学特性基本不变,易于长期保存,加水后能恢复到冻干前的形态,并且能保持原有的生物学特性。
本发明针对现有技术的不足,采用喷雾冷冻干燥法制备索玛鲁肽微粒,获得的产品是球型、表面和内部多孔的粉状或颗粒状产品,完全区别于喷雾干燥的中孔的、团聚型的产品和经干燥并粉碎而成的片状、菱状、针状的冷冻干燥产品,产品具有较好的稳定性和复水性,可用于索玛鲁肽口服固体制剂的制备。
发明内容
本发明采用喷雾冷冻干燥技术进行索玛鲁肽的干燥,所得的索玛鲁肽产品收率高,产品粒度符合既定要求,同时很好的保证了产品的质量,样品稳定,达到了良好的技术效果。
一种基于喷雾冷冻干燥工艺的索玛鲁肽微粒的制备方法,包括以下步骤:
A、配制索玛鲁肽或其盐的含量为1-10%(w/w)的水溶液,预先冷却;
B、将以上料液通过雾化器将其雾化,并与降温后的空气或氮气充分接触冷却,得到冰晶颗粒,冰晶颗粒进行真空冷冻干燥得到索玛鲁肽微粒;
雾化器雾化的条件为:进料温度为0-10℃,进口空气或氮气温度为-30~-70℃;雾化气流速(kg/h)与索玛鲁肽溶液进液流速(kg/h)的比值为1.0~3.0;
真空冷冻干燥条件为:在-30~-10℃维持1小时,冷凝器温度为-40~-80℃,抽真空至真空度≤100pa,在2小时内升温至0℃,又经过4小时升温至20~40℃进行解析干燥,并维持2-10小时;
喷雾冷冻干燥制备得到的索玛鲁肽微粒粒径为1~100μm,纯度>99.0%,单个杂质<0.10%,可用于索玛鲁肽口服片剂的制备。
喷雾冷冻干燥制备得到的索玛鲁肽微粒扫描电镜图谱和有关物质图谱见附图1和2。
附图说明
图1为索玛鲁肽微粒扫描电镜图谱
图2为索玛鲁肽微粒有关物质图谱
具体实施方式
实施例1
称取索玛鲁肽2.0g,溶于100ml水中,降温至5℃,喷雾冷冻干燥设备进口温度降至-40℃,雾化气流速为3kg/h,进料速度为1kg/h,采用0.7mm喷头,进行雾化冷却,喷雾结束后,收集桶在-30℃维持1小时,抽真空至真空度≤100pa,在2小时内升温至0℃,又经过4小时升温至30℃,并维持6小时,制得索玛鲁肽微粒1.8g,收率90%。
实施例2
称取索玛鲁肽10.0g,溶于200ml水中,降温至2℃,喷雾冷冻干燥设备进口温度降至-50℃,雾化气流速为2kg/h,进料速度为1kg/h,采用0.5mm喷头,进行雾化冷却,喷雾结束后,收集桶在-30℃维持1小时,抽真空至真空度≤100pa,在2小时内升温至0℃,又经过4小时升温至30℃,并维持8小时,制得索玛鲁肽微粒9.4g,收率94%。
实施例3
称取索玛鲁肽5.0g,溶于120ml水中,降温至5℃,喷雾冷冻干燥设备进口温度降至-60℃,雾化气流速为1.5kg/h,进料速度为0.8kg/h,采用0.5mm喷头,进行雾化冷却,喷雾结束后,收集桶在-20℃维持1小时,抽真空至真空度≤100pa,在2小时内升温至0℃,又经过4小时升温至25℃,并维持6小时,制得索玛鲁肽微粒4.6g,收率92%。
Claims (9)
1.一种基于喷雾冷冻干燥工艺的索玛鲁肽微粒的制备方法,其特征在于:包括以下步骤:
A、配制索玛鲁肽或其盐的水溶液,预先冷却;
B、将以上料液通过雾化器将其雾化,并与降温后的空气或氮气充分接触冷却,得到冰晶颗粒,冰晶颗粒进行真空冷冻干燥得到索玛鲁肽微粒。
2.根据权利要求1所述的制备方法,其特征在于:所述A步骤中制得的索玛鲁肽水溶液含量为1-10%(w/w)。
3.根据权利要求1所述的制备方法,其特征在于:所述的雾化条件为:进料温度为0-10℃,进口空气或氮气温度为-30~-70℃,优选-40~-50℃。
4.根据权利要求1所述的制备方法,其特征在于:雾化过程中,雾化气流速(kg/h)与索玛鲁肽溶液进液流速(kg/h)的比值为1.0~3.0。
5.根据权利要求1所述的制备方法,其特征在于:所述真空冷冻干燥条件为:在-30~-10℃维持1小时,冷凝器温度为-40~-80℃,抽真空至真空度≤100pa,在2小时内升温至0℃,又经过4小时升温至20~40℃进行解析干燥,并维持2-10小时。
6.根据权利要求3所述的制备方法,其特征在于:进口雾化气体为空气或氮气,优选氮气。
7.根据权利要求5所述的制备方法,其特征在于:所述冷冻干燥的解析干燥温度为20~40℃,优选30℃。
8.根据权利要求5所述的制备方法,其特征在于:所述冷冻干燥的解析干燥时间为2-10小时,优选6小时。
9.根据权利要求1所述的制备方法,其特征在于:喷雾冷冻干燥制备得到的索玛鲁肽粒径为1-100μm,采用此方法制备的索玛鲁肽微粒可用于索玛鲁肽口服片剂的制备。
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CN116159027A (zh) * | 2022-12-29 | 2023-05-26 | 江苏诺泰澳赛诺生物制药股份有限公司 | 一种司美格鲁肽冻干药物组合物及其制备方法 |
CN117084985A (zh) * | 2023-10-20 | 2023-11-21 | 天津凯莱英医药科技发展有限公司 | 胸腺法新颗粒及其制备方法 |
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