CN115212322B - 一种用于放射性药物制备的冻干药盒及其制备方法 - Google Patents
一种用于放射性药物制备的冻干药盒及其制备方法 Download PDFInfo
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- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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Abstract
本发明涉及放射性药物技术领域,具体涉及一种用于放射性药物制备的冻干药盒及其制备方法。本发明所提供的冻干药盒由生长抑素肽类似物NODAGA‑JR11、邻菲罗啉、龙胆酸、甘露醇和注射用水组成;所述的生长抑素肽类似物NODAGA‑JR11、邻菲罗啉、龙胆酸和甘露醇的质量比为0.001‑0.005:0.0001‑0.0005:0.0001‑0.0005:1‑10。本发明制备得到的冻干药盒稳定性好,既可以保证药盒的稳定性以便于储存和运输、又可以保证即时标记药物的质量满足临床使用要求。
Description
技术领域
本发明涉及放射性药物技术领域,具体涉及一种用于放射性药物制备的冻干药盒及其制备方法。
背景技术
生长抑素受体(Somatostatin Receptor,SSTR)广泛存在于人体肿瘤中,绝大多数神经内分泌肿瘤、胃肠胰内分泌肿瘤含有SSTR,如垂体瘤、脑膜瘤、髓样甲状腺瘤、胰腺癌、胰岛细胞癌等。此外,在小细胞肺癌、非霍奇金淋巴瘤、肾细胞癌、霍奇金淋巴瘤等多种肿瘤组织中SSTR也有较高的表达。
目前,SSTR已成为多种肿瘤诊治的一个有效靶点,特别是神经内分泌肿瘤(Neuroendocrine Tumors,NET)发生发展分子机制研究及治疗的靶点之一。临床应用生长抑素类似物(Somatostatin Analog,SSA)控制NET增殖,缓解激素引起的相应症状。SSTR显像可反映靶病灶SSTR的表达和分布情况,而PET/CT(正电子发射计算机断层显像)是核医学显像的一种方式。它可以在分子或细胞水平揭示疾病早期发生和发展的情况,是NET和其它肿瘤早期显像诊断的强大手段。
目前临床主要应用受体激动剂,以68Ga-DOTATATE为代表,其已于2016年由美国食品药品监督管理局(Food and Drug Administration,FDA)批准用于NET的诊断。最近的研究表明,SSTR拮抗剂不触发内化机制,且结合受体后不易解离,更适合作为SSTR PET显像剂。从第1代SSTR拮抗剂BASS(pNO2-Phe-c(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2)到近些年的LM3(p-Cl-Phe-c[D-CysTyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2)、JR11(Cpa-c[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2),相关研究表明SSTR拮抗剂比激动剂能识别更多的结合位点,虽体外亲和性略低,但肿瘤摄取更多,且本底低,有助于NET肝微小转移灶或肠道病灶的检出。但目前未发现Ga-68标记冻干药盒得到最终放射性药物的报道。
发明内容
本发明的目的是提供一种68Ga标记冻干药盒。
第一方面,本发明提供一种用于放射性药物制备的冻干药盒,所述冻干药盒的原料包括生长抑素肽类似物NODAGA-JR11、金属掩蔽剂、抗氧化剂、赋形剂和注射用水。
在本发明所提供的冻干药盒中,生长抑素肽类似物NODAGA-JR11、金属掩蔽剂、抗氧化剂、赋形剂的质量比为0.001-0.005:0.0001-0.0005:0.0001-0.0005:1-10。
在本发明所提供的冻干药盒中,所述金属掩蔽剂包括邻菲罗啉、所述抗氧化剂包括龙胆酸、所述赋形剂包括甘露醇。在本发明所提供的冻干药盒中,所述生长抑素肽类似物NODAGA-JR11、邻菲罗啉、龙胆酸、甘露醇的质量比为0.001-0.005:0.0001-0.0005:0.0001-0.0005:1-10。
在本发明所提供的冻干药盒中,所述放射性药物标记所用的放射性元素为放射性镓。
根据本领域技术人员的理解,本发明还请求保护,上述的冻干药盒在提高标记药物的放射化学纯度中的应用。
第二方面,本发明提供上述的冻干药盒的制备方法,包括:
(1)将生长抑素类似物NODAGA-JR11、龙胆酸、邻菲罗啉和甘露醇分别用超纯水溶解;
(2)将(1)中各个溶液混合均匀、灭菌过滤、分装,冷冻干燥。
本发明所提供的冻干药盒的制备方法中,冷冻干燥条件是:在8小时内,将混合溶液的温度,从-30℃升至20℃,逐渐去除水分。
在本发明所提供的制备方法中,所述生长抑素类似物NODAGA-JR11的用量为5μg-100μg、所述龙胆酸的用量为1.25μg-25μg、所述邻菲罗啉的用量为1.25μg-25μg、所述甘露醇的用量为5mg-100mg。
第三方面,本发明还提供上述冻干药盒的使用方法,使用68Ga对上述的冻干药盒进行配位络合。
在本发明所提供的使用方法中,调节冻干药盒中的pH为2.5-4.5,取68GaCl3溶液注入所述的冻干药盒中进行标记;
在密封条件下置金属浴(20-40℃)中加热10-20分钟,取出后冷却至室温。
在本发明所提供的使用方法中,调节pH为2.5-4.5的方法为:将甲酸钠或醋酸钠缓冲液注入所述的冻干药盒中,调节pH为2.5-4.5。
根据本领域技术人员的理解,本发明还请求保护上述的使用方法得到的68Ga标记的冻干药盒在提高肿瘤检测准确性中的应用。
本发明公开了一种制备放射性药物的冻干药盒及其制备方法和应用。冻干药盒由生长抑素肽类似物NODAGA-JR11、邻菲罗啉、龙胆酸、甘露醇和注射用水组成;所述的生长抑素肽类似物NODAGA-JR11、邻菲罗啉、龙胆酸和甘露醇的质量比为0.001-0.005:0.0001-0.0005:0.0001-0.0005:1-10。制备方法包括:(1)按处方量称取生长抑素肽类似物NODAGA-JR11、邻菲罗啉、龙胆酸和甘露醇,分别用灭菌注射用水溶解;(2)将(1)中溶液混合均匀、过滤、分装、冷冻干燥、压盖密封,得到制备放射性药物的冻干药盒。
本发明的有益效果在于:
本发明制备的68Ga标记冻干药盒是由多种组分组成的即时标记用药盒,配方中除主原料外,主要包含赋形剂、抗氧化剂等,以保证标记药物的放射化学纯度。临床使用要求药物的放射性标记过程简单、耗时短,通过冻干药盒进行的标记,无需再对药物进行额外的分离纯化,将大大缩短放射性标记时间。同时,冻干药盒稳定性好,既可以保证药盒的稳定性以便于储存和运输、又可以保证即时标记药物的质量满足临床使用要求。因此,由Ga-68标记的冻干药盒有利于普及使用并具有广阔的应用前景。
本发明的制备放射性药物的冻干药盒稳定性好、放射化学纯度高,同时制备方法简单快捷;而且制备的冻干药盒经试验表明常温条件下(25℃)至少可以保存12个月,稳定性良好。
附图说明
图1为本发明实施例1中,NODAGA-JR11的HPLC谱图。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1生长抑素肽类似物NODAGA-JR11的合成
1.称量取代度为0.3mmol/g的Fmoc-Thr(tBu)-CTC Resin 1g,20%Pip/DMF脱保护30mins;
2.按当量比例投入原料(AA:HBTU:NMM=3:2.85:6),加入适量DMF,鼓氮气反应30min,树脂取样茚三酮检测透明,DMF,DCM,甲醇依次洗涤;
3.重复1,2步骤,得到Cpa-c[DCys(Boc)-Aph(Hor)-D-Aph(Cbm)-Lys(Boc)-Thr(tBu)-Cys(Boc)]-D-Tyr-CTC Resin;
4.将树脂肽置于30%HFIP/DCM中,摇床控温1h,抽滤,收集滤液,旋蒸浓缩得到粗品Cpa-c[DCys(Boc)-Aph(Hor)-D-Aph(Cbm)-Lys(Boc)-Thr(tBu)-Cys(Boc)]-D-Tyr(tBu);
5.将NODAGA溶解于DMF中,加入1.2equiv的EDC.HCl和HOSu,然后加入粗品,搅拌过夜,浓缩后处理得到NODAGA-Cpa-c[DCys(Boc)-Aph(Hor)-D-Aph(Cbm)-Lys(Boc)-Thr(tBu)-Cys(Boc)]-D-Tyr(tBu);
6.甲醇洗涤后抽干反应器内树脂,转移至切割管中,加入TFA/E DT/H2O=95/2.5/2.5切割液,摇床控温3h;
7.抽滤,将切割滤液收集至离心管中,加入到6倍体积冰乙醚中,离心机沉淀收集固体,将沉淀的粗品用乙醚洗3遍,得到粗品NODA GA-4Cpa-DCys-4-Aph(L-Hor)-D4Aph(Cbm)-Lys-DThr-Cys-Tyr-NH2;
8.将中间体溶解于水和乙腈中,加入碘进行氧化,氧化后,进一步的反相HPLC纯化,得到最后的精品NODAGA-4Cpa-DCys-4-Aph(L-Hor)-D4Aph(Cbm)-Lys-DThr-Cys-Tyr-NH2(DCys&Cys Bridge)。
实施例2NODAGA-JR11的表征
(1)经Fmoc固相合成法,通过氨基酸缩合、树脂上多肽的切除、多肽的环化、反相HPLC分离纯化,得到最终的产品NODAGA-JR11。NODAGA-JR11的高效液相分析图谱如图1所示,由图可知,DOTA-JR11的HPLC纯度为96.6%。
(2)NODAGA-JR11的质谱图显示m/z 830.8,电荷数为2,通过计算分子量为:1659.6。NODAGA-JR11的理论分子量为:1660.3。说明制备得到的多肽的分子量与NODAGA-JR11理论分子量相符。
实施例3NODAGA-JR11冻干药盒的制备1
(1)将5μg生长抑素类似物NODAGA-JR11(实施例1制备所得)、1.25μg龙胆酸、1.25μg邻菲罗啉和5mg甘露醇分别用超纯水溶解;
(2)将(1)中各个溶液混合均匀、灭菌过滤、分装至西林瓶中、冷冻干燥、冷冻干燥的条件为:冷冻干燥-30℃至20℃,梯度升温8小时去除注射用水。
(3)压盖密封,得到制备放射性药物的冻干药盒。
实施例4NODAGA-JR11冻干药盒的制备2
(1)将20μg生长抑素类似物NODAGA-JR11(实施例1制备所得)、5μg龙胆酸、5μg邻菲罗啉和20mg甘露醇分别用超纯水溶解;
(2)将(1)中各个溶液混合均匀、灭菌过滤、分装至西林瓶中、冷冻干燥、冷冻干燥的条件为:冷冻干燥-30℃至20℃,梯度升温8小时去除注射用水;
(3)压盖密封,得到制备放射性药物的冻干药盒。
实施例5NODAGA-JR11冻干药盒的制备3
(1)将100μg生长抑素类似物NODAGA-JR11(实施例1制备所得)、25μg龙胆酸、25μg邻菲罗啉和100mg甘露醇分别用超纯水溶解;
(2)将(1)中各个溶液混合均匀、灭菌过滤、分装至西林瓶中、冷冻干燥、冷冻干燥的条件为:冷冻干燥-30℃至20℃,梯度升温8小时去除注射用水;
(3)压盖密封,得到制备放射性药物的冻干药盒。
实施例6 68Ga-NODAGA-JR11的制备
将实施例3制备的放射性药物的冻干药盒用于68Ga配位络合,包括:取68GaCl3溶液注入所述的冻干药盒中进行标记,再将甲酸钠或醋酸钠缓冲液注入所述的冻干药盒中调节pH为2.5-4.5。
在密封条件下置金属浴(20-40℃)中加热10~20分钟,取出后冷却至室温,制得68Ga-NODAGA-JR11制剂。
实施例7 68Ga-NODAGA-JR11的生物学评价应用
(1)制备的68Ga-NODAGA-JR11制剂用于荷AR42J肿瘤裸鼠中的小动物PET/CT显像研究,AR42J是大鼠胰腺外分泌腺肿瘤细胞。
(2)显像研究时,取0.10mL(3.0-5.0MBq)的68Ga-NODAGA-JR11通过尾静脉注射到荷AR42J肿瘤裸鼠中。麻醉后(异氟烷)的动物俯卧式固定在动物PET扫描仪上,分别选取注射后30min、60min、120min三个时间点进行PET-CT扫描,每次PET扫描10min,CT扫描3min,之后将PET和CT影像拟合,获得静态PET-CT影像。
(3)显像结果显示,68Ga-NODAGA-JR11在荷瘤裸鼠体内主要分布在肾脏和膀胱,与动物分布实验结果一致,该标记物主要通过肾脏排泄。在其它非靶器官摄取较低,在肿瘤部位有较高摄取,可以清晰看到肿瘤的位置。
对比例1不同冻干条件下,68Ga-NODAGA-JR11的稳定性效果
本对比例提供的68Ga-NODAGA-JR11的制备方法与实施例6相同,区别在于,本对比例采用的冻干药盒的冻干条件与实施例3中不同。
其中,对照组1中冻干条件为:-10-10℃(梯度升温8小时去除水分)。
对照组2中冻干条件为:-50℃至-30℃,(梯度升温8小时去除水分)。
本对比例中,采用上面所述的68Ga标记方法,检测实施例6和对照组1和对照组2结果表明68Ga-NODAGA-JR11放射化学纯度均小于95%,不满足质量要求。
对比例2不同pH下,68Ga标记的效果
本对比例与实施例6相同,将实施例3制备的放射性药物的冻干药盒用于68Ga配位络合,区别在于,本对比例中分别将冻干药盒的pH调节至2和5,其中pH为2作为对照组3、pH为5作为对照组4。
采用上面所述的68Ga标记方法,对本对比例制备得到的68Ga-NODAGA-JR11进行检测,结果表明,当pH为2时,所得到的68Ga-NODAGA-JR11放射化学纯度小于95%,当pH为5时,所得到的68Ga-NODAGA-JR11放射化学纯度同样小于95%。
对比例3原料不同用量
本对比例中采用与实施例3相同的方法进行N ODAGA-JR11冻干药盒的制备,区别在于,本对比例中各原料的用量与实施例3不同。其中,对照组5中,生长抑素类似物NODAGA-JR11的用量为5μg、龙胆酸的用量为2μg、邻菲罗啉的用量为2μg、甘露醇的用量为5mg。
对照组6中,生长抑素类似物NODAGA-JR11的用量为20μg、龙胆酸的用量为5μg、邻菲罗啉的用量为5μg、甘露醇的用量为20mg。
采用上面所述的标记方法,对对照组5和对照组6的效果进行检测,结果表明对照组6的68Ga-NODAGA-JR11放射化学纯度可以达到95%,而对照组5的68Ga-NODAGA-JR11放射化学纯度低于95%。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (6)
1.一种用于放射性药物制备的冻干药盒,其特征在于,所述冻干药盒的原料中生长抑素肽类似物NODAGA-JR11用量为20-100μg、邻菲罗啉的用量为5-25μg、龙胆酸的用量为5-25μg、甘露醇的用量为20-100mg;
将生长抑素类似物NODAGA-JR11、龙胆酸、邻菲罗啉和甘露醇分别用超纯水溶解,混合均匀、灭菌过滤、分装,冷冻干燥;所述冷冻干燥条件是在8小时内,将混合溶液的温度,从-30℃升至20℃,逐渐去除水分;
使用放射性镓对所述的冻干药盒进行配位络合时,调节冻干药盒中的pH为2.5-4.5。
2.根据权利要求1所述的冻干药盒,其特征在于,所述放射性镓为68Ga。
3.权利要求1-2任一项所述的冻干药盒在提高放射性标记药物的放射化学纯度中的应用。
4.使用68Ga标记权利要求1-2任一项所述的冻干药盒的方法,其特征在于,调节冻干药盒中的pH为2.5-4.5,取68GaCl3溶液注入所述的冻干药盒中进行标记;
在密封条件下置金属浴,在20-40℃中加热10-20分钟,取出后冷却至室温。
5.根据权利要求4所述的方法,其特征在于,调节pH为2.5-4.5的方法为:将甲酸钠或醋酸钠缓冲液注入所述的冻干药盒中,调节pH为2.5-4.5。
6.权利要求4-5任一项所述的方法得到的68Ga标记的冻干药盒在制备提高肿瘤检测准确性药物中的应用。
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