CN116803393B - 一种pan-HER抑制剂的药物组合物及其制备方法 - Google Patents
一种pan-HER抑制剂的药物组合物及其制备方法 Download PDFInfo
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- CN116803393B CN116803393B CN202311071266.0A CN202311071266A CN116803393B CN 116803393 B CN116803393 B CN 116803393B CN 202311071266 A CN202311071266 A CN 202311071266A CN 116803393 B CN116803393 B CN 116803393B
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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
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Abstract
本发明属于药物制剂领域,具体涉及一种pan‑HER抑制剂的药物组合物及其制备方法,本发明提供了一种pan‑HER抑制剂的药物组合物,所述药物组合物含有式Ⅰ化合物或其药学上可接受的盐0.1~0.4%w/v,磷脂1~6%w/v,胆固醇0.2~1%w/v,聚乙二醇或聚乙二醇化磷脂0.1~0.5%w/v,冻干保护剂5~20% w/v,余量为注射用水。本发明药物组合物针对活性药物成分水溶性不好,生物利用度不佳以及不良反应严重的问题,采用脂质体技术包封活性成分,平均粒度分布达到70~150nm,同时选用科学合理的辅料,提高药物生物利用度,减轻不良反应。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种pan-HER抑制剂的药物组合物及其制备方法。
背景技术
人类表皮生长因子受体(HER ,EGFR)是蛋白酪氨酸激酶家族的一员,广泛分布于人体各组织细胞膜上,可以调节细胞的增殖,生长,转移和凋亡。其结构由三部分组成:胞外的配体结合区、跨膜区以及胞内的酪氨酸激酶区。根据受体的结构差异,可以将HER区分为四种亚型,分别为HER1(EGFR , ErbB-1)、HER2(ErbB-2)、HER3(ErbB-3)及HER4(ErbB-4)。研究发现,HER 在乳腺癌、非小细胞肺癌、胃癌、胰腺癌、卵巢癌、结直肠癌、头颈部鳞癌、恶性胶质瘤以及***癌等多种肿瘤细胞中均存在过表达或异常激活的现象。另外,研究表明,HER的过表达或异常激活与肿瘤的分化程度、恶性程度及预后等密切相关。因此,抑制HER成为了抗肿瘤药物研究的热点。
目前,已经上市的靶向性的HER抑制剂包括吉非替尼(Gefitinib) 、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)等。CN 111630046A公开了一种对HER1、HER2和HER4抑制活性明显的pan-HER抑制剂,有必要对于其给药形成进行充分的研究,以便将其转化成具备较高生物利用度的产品,使其在临床上具有良好的应用。
发明内容
本发明的目的在于提供一种生物利用度高、不良反应少的pan-HER抑制剂的药物组合物。
为了实现上述目的,本发明采用的技术方案如下:
本发明提供一种pan-HER抑制剂的药物组合物,所述药物组合物以式Ⅰ所示化合物或其药学上可接受的盐为活性药物,所述药物组合物含有以下成分:
式Ⅰ化合物或其药学上可接受的盐0.1~0.4%w/v,
,
磷脂1~6%w/v,
胆固醇0.2~1%w/v,
聚乙二醇或聚乙二醇化磷脂 0.1~0.5%w/v,
冻干保护剂5~20% w/v,
余量为注射用水。
进一步,所述药物组合物中药脂比为1:4~20w/w,磷脂和胆固醇比为2~12:1w/w。
优选的,所述药物组合物中药脂比为1:6~14 w/w,磷脂和胆固醇比为4~8:1w/w。
更优选,所述药物组合物中药脂比为1:12.5w/w,磷脂和胆固醇比为6:1w/w。
本发明所述磷脂可以为大豆磷脂、氢化大豆卵磷脂、蛋黄卵磷脂、氢化蛋黄卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸肌醇、鞘磷脂、二硬脂酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、二棕榈酰磷脂酰甘油、二油酰磷脂酰胆碱中的任意一种或其任意组合,但不局限于此。
进一步,所述聚乙二醇化磷脂选自二芥酰基磷脂乙醇胺-聚乙二醇(DEPE-PEG)、二硬脂酰磷脂乙醇胺-聚乙二醇(DSPE-PEG)、胆固醇-聚乙二醇(Chol-PEG)、 二硬脂酰基磷脂酰胆碱-聚乙二醇(DSPC-PEG)、磷脂酰乙醇胺-聚乙二醇(PE-PEG)、磷脂酰胆碱-聚乙二醇(PC-PEG)中的一种或其任意组合。优选为二芥酰基磷脂乙醇胺-聚乙二醇(DEPE-PEG)、二硬脂酰磷脂乙醇胺-聚乙二醇(DSPE-PEG)中的一种或其任意组合。
进一步,所述聚乙二醇或聚乙二醇化磷脂,其聚乙二醇的分子量为800~20000 Da,优选为1000~8000 Da。
本发明所述冻干保护剂,可以为蔗糖、乳糖、海藻糖、麦芽糖、葡萄糖、甘露醇、山梨醇、木糖醇、赤藓糖醇、苏氨酸中的一种或其任意组合,但不局限于此;优选为蔗糖、海藻糖、甘露醇中的一种或其任意组合。
进一步,所述药物组合物采用薄膜分散法、注入法、超声波分散法、薄膜-超声分散法制备。
本发明还提供了优选的所述药物组合物的制备方法,包括如下步骤:
(1)称取活性药物,磷脂,聚乙二醇或聚乙二醇化磷脂,胆固醇置于有机溶媒中,在40~60℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入40~60℃的注射用水中,搅拌水化,得脂质体溶液粗品,去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行整粒,得脂质体溶液;
(3)称取冻干保护剂,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
进一步,所述步骤(1)有机溶媒选自无水乙醇、无水***、氯仿和甲醇中的一种或两种。
进一步,所述步骤(2)去除脂质体溶液粗品中有机溶媒的方法为超滤或减压浓缩。
进一步,所述步骤(2)整粒的方法为挤出法或均质法。
进一步,所述挤出法使用挤出膜孔径选自0.6μm、0.4μm、0.2μm、0.1μm、0.08μm、0.5μm中的一种。
进一步,所述均质法采用均质机,均质压力200bar~1500bar。
本发明的有益效果如下:
本发明提供的pan-HER抑制剂的药物组合物,针对活性药物成分水溶性不好,生物利用度不高以及不良反应严重的问题,采用脂质体技术包封活性成分,平均粒度分布达到70~150nm,同时选用科学合理的辅料,提高药物生物利用度,并减轻不良反应。
实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例对本发明进行具体描述,有必要指出的是,以下实施例仅用于对本发明进行解释和说明,并不用于限定本发明。本领域技术人员根据上述发明内容所做出的一些非本质的改进和调整,仍属于本发明的保护范围。
以下实施例中活性药物API为式Ⅰ所示化合物,简称为JRF103。
实施例1 制备不同JRF103纳米制剂
制备JRF103纳米混悬冻干剂(NS)
称取JRF103原料药 2g和大豆磷脂1.5g溶解于25ml无水乙醇中,搅拌溶解后1ml注射器吸取有机相,在500r/m搅拌速度下快速注入纯净水中,有机相与水相比例1%(v/v),继续搅拌10min,取粗混悬液过高压均质机800bar 25个循环,检测混悬粒子粒径为172.1±4.2nm。按照浓度0.15g/ml加入蔗糖,搅拌溶解后冷冻干燥,得到JRF103纳米混悬冻干剂。
制备JRF103纳米晶体(NN)
称取JRF103 原料药2g,溶解于20ml无水乙醇中,得到的溶液作为有机相,将PVA0.9g加入到0.9L蒸馏水中,室温下膨胀后超声溶解作为水相,室温下,用注射器将有机相缓慢注入水相中,有机相与水相比例1:20,伴随搅拌混合10min后,于100MPa均质20个循环,随后离心1h,除去有机溶剂,沉淀分散在蒸馏水中超声洗涤三次,干燥后得到JRF103纳米晶体。检测其平均粒径为152.5±3.8nm。
制备JRF103脂质体冻干粉(Lip)
取大豆磷脂32g、胆固醇5g、磷脂酰胆碱-聚乙二醇(PC-PEG2000) 4g、JRF103原料药 2g,混合均匀,加入无水乙醇充分溶解,在35℃和120 rpm旋转蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂。向磷脂薄膜中加入注射用水,于60℃和1000rpm下磁力搅拌1 h,1000bar压力均质,得到脂质体溶液;冻干保护剂蔗糖50g,用注射用水溶解后加入脂质体溶液,用注射用水定容至1000ml,检测其平均粒径为132.6±3.2nm。搅拌混匀,用0.22μm滤器过滤,分装,冻干,即得。
制备JRF103纳米胶束冻干粉(NM)
称取JRF103 原料药2g,8g聚乳酸羟基乙酸共聚物、4g二硬脂酰磷脂酰乙醇胺-聚乙二醇、4g大豆磷脂放入400ml无水乙醇中,溶解完全后减压蒸发溶剂,得到一层均匀薄膜,真空干燥去除有机溶剂,加入5%葡萄糖溶液水化,超声10min,检测其平均粒径为135±44nm,按照浓度0.15g/ml加入蔗糖,搅拌溶解后冷冻干燥,得到JRF103纳米胶束冻干粉。
实施例2 不同JRF103纳米制剂药动学研究
JRF103水溶性较差,水中溶解度仅为0.005mg/L,以13%乙醇溶液溶解JRF103,并添加0.2%吐温80制备JRF103注射液作为对照组,与实施例1制备的纳米制剂(命名为NS组、NN组、Lip组、NM组)进行体内药动学研究。
方法为:准备50只SD大鼠,随机分为5组,分别进行颈静脉插管。分别静脉注射给予JRF103注射液,以及NS组、NN组、Lip组、NM组溶液(均将制剂以注射用水复溶),给药量为2mg/kg,于给药前及给药后5、15、30、60、120、240、360、540和720min颈静脉取血,肝素抗凝,3000rpm离心10min,分离血浆,测定血浆中药物浓度。计算消除半衰期(t1/2)和曲线下面积(AUC)。结果见表1。
表1 不同JRF103纳米制剂体内药动学结果
处方 | t1/2(h) | AUC0→t(ng*h/ml) | AUC0→inf(ng*h/ml) |
JRF103注射液 | 2.13 | 2960 | 2980 |
NS组 | 2.84 | 3821 | 3888 |
NN组 | 2.36 | 3204 | 3330 |
Lip组 | 3.58 | 4383 | 4417 |
NM组 | 3.14 | 3715 | 3823 |
上表结果显示,JRF103注射液半衰期较短,AUC值较低,虽然各组纳米制剂都不同程度的提高了JRF103 的t 1/2和AUC值,但Lip组的t 1/2最长,并且AUC最高。
实施例3 不同药脂比对脂质体的影响
按照表2处方,以及实施例1 所述薄膜分散法制备脂质体冻干剂。用注射用水复溶制备的冻干粉,得到复溶液,测定其药物包封率。结果见表2。
表2 不同药脂比对脂质体性能的影响
表2表明,处方1药脂比过高,浓缩时溶液中有固体析出,包封率低;处方4药脂比1:12.5,包封率最高;处方7脂质含量过大,包封率变化不明显,但该药脂比范围下过滤阻力较大,药脂比1:4-20较为适宜,优选1:6-14,更优选为1:12.5。
实施例4 不同磷脂与胆固醇比例对脂质体的影响
按照表3处方,以及实施例1 所述薄膜分散法制备脂质体冻干粉,注射用水复溶,测定包封率、电位以及粒径,结果见表3。
表3不同磷脂与胆固醇比例对脂质体性能的影响
表3表明,不同磷脂与胆固醇比例对脂质体包封率、粒径分布和PDI有影响,比例过高或过低包封率均会降低,磷脂和胆固醇比为2~12:1w/w时包封率高于80%,优选4~8:1w/w,包封率高于85%,最优选为6:1。
实施例5 不同PEG或PEG化磷脂对脂质体的影响
按照表4处方,以及实施例1所述薄膜分散法制备脂质体冻干剂。处方15-21使用不同的PEG或者PEG化磷脂,包括聚乙二醇2000(PEG2000)、磷脂酰乙醇胺-聚乙二醇2000(PE-PEG2000)、二硬脂酰基磷脂酰胆碱-聚乙二醇2000(DSPC-PEG2000)、二硬脂酰磷脂乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二芥酰基磷脂乙醇胺-聚乙二醇2000(DEPE-PEG2000)、胆固醇-聚乙二醇2000(Chol-PEG2000)、磷脂酰胆碱-聚乙二醇(PC-PEG)。
表4 不同PEG或PEG化磷脂脂质体处方
按照实施例2所述方法测定处方11、处方15-21的药代动力学,结果见表5。
表5 不同PEG或PEG化磷脂的脂质体体内药动学结果
处方 | t1/2(h) | AUC0→t(ng*h/ml) | AUC0→inf(ng*h/ml) |
11 | 3.36 | 4051 | 4153 |
15 | 3.52 | 4652 | 4627 |
16 | 3.72 | 5018 | 5264 |
17 | 3.69 | 5164 | 5177 |
18 | 3.88 | 5261 | 5316 |
19 | 4.57 | 6893 | 6890 |
20 | 4.78 | 7183 | 7232 |
21 | 4.05 | 4862 | 4870 |
表5表明,处方11、处方15-21均具有较好的体内药动学结果,其中处方19和处方20的AUC结果显著优于其他配方,表明含有二芥酰基磷脂乙醇胺-聚乙二醇或者含二硬脂酰磷脂乙醇胺-聚乙二醇的JRF103脂质体从体内消除时间更长,并且AUC更大。
实施例6 不良反应检测
取SD大鼠50只,随机分成5组,每组10只。一组SD大鼠重复静脉注射给予1.0mg/kg的JRF103注射液,其他组SD大鼠分别重复静脉注射给予1.0mg/kg处方16-20制备的JRF103脂质体冻干粉(均以注射用水复溶),每天1次,连续给药28天,观察并记录不良反应,结果见表6。
表6 单次给药毒性研究
不良反应 | JRF103注射液 | 处方16 | 处方17 | 处方18 | 处方19 | 处方20 |
死亡例数 | 0 | 0 | 0 | 0 | 0 | 0 |
体重下降 | ++ | + | — | + | — | — |
摄食量下降 | +++ | + | + | + | — | — |
水样便/软便 | +++ | ++ | ++ | + | + | + |
口鼻周围呈红色物质 | ++ | + | — | + | — | — |
弓背消瘦 | ++ | — | + | + | — | — |
毛发稀少 | ++ | + | + | + | + | — |
*注:评价不良反应程度,“++”症状较为明显,“+”症状轻微,“—”无明显症状。
结果可见,JRF103注射液以及处方16-20均未出现死亡例,JRF103脂质体的动物组较注射JRF103溶液的动物组,不良反应更少更轻微,尤其是处方19和20。本发明的JRF103脂质体冻干粉可有效降低JRF103药物的毒副作用,成药前景良好。
实施例7 不同制备方法对脂质体的影响
按照实施例5处方19制备脂质体冻干粉,分别以实施例1所述薄膜分散法,以及注入法制备,注入法具体步骤如下:
(1)称取JRF103,大豆磷脂,DSPE-PEG2000,胆固醇置于无水乙醇中,在50℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入50℃的注射用水中,搅拌水化,得脂质体溶液粗品,减压浓缩去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行均质,均质压力1000bar,得脂质体溶液;
(3)称取冻干保护剂,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
对不同方法制备得到的冻干粉进行复溶实验,测定复溶时间,结果薄膜分散法制备的冻干粉复溶时间较慢(大于5s),而注入法制备的冻干粉复溶时间为较快(低于5s)。同时对复溶后的溶液进行脂质体粒径、电位和包封率的检测,结果两种制备方法制备的冻干粉复溶后都能形成粒径小、包封率高且性能优异的脂质体,符合用药需求。
实施例8
按照以下方法制备JRF103脂质体冻干剂。
处方:JRF103 4g,蛋黄卵磷脂40g,胆固醇6g,DEPE-PEG1000 3g,蔗糖80g。
制备方法:
(1)称取JRF103,蛋黄卵磷脂,DEPE-PEG1000,胆固醇置于甲醇中,在40℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入40℃的注射用水中,搅拌水化,得脂质体溶液粗品,减压浓缩去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行均质,均质压力1000bar,得脂质体溶液;
(3)称取冻干保护剂蔗糖,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
实施例9
按照以下方法制备JRF103脂质体冻干剂。
处方:JRF103 3g,氢化大豆卵磷脂32g,胆固醇5.2g,DEPE-PEG5000 2g,海藻糖100g。
制备方法:
(1)称取JRF103,氢化大豆卵磷脂,DEPE-PEG5000,胆固醇置于无水乙醇中,在60℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入60℃的注射用水中,搅拌水化,得脂质体溶液粗品,减压浓缩去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行均质,均质压力1200bar,得脂质体溶液;
(3)称取冻干保护剂海藻糖,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
实施例10
按照以下方法制备JRF103脂质体冻干剂。
处方:JRF103 3.5g,磷脂酰甘油44g,胆固醇5.8 g,DSPC-PEG3400 2.5g,海藻糖50g、甘露醇50g。
制备方法:
(1)称取JRF103,磷脂酰甘油,DSPC-PEG3400,胆固醇置于无水乙醇中,在50℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入50℃的注射用水中,搅拌水化,得脂质体溶液粗品,减压浓缩去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行均质,均质压力1200bar,得脂质体溶液;
(3)称取冻干保护剂海藻糖和甘露醇,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
实施例11
按照以下方法制备JRF103脂质体冻干剂。
处方:JRF103 3.8g,二油酰磷脂酰乙醇胺46g,胆固醇5.2g,DSPE-PEG 1000 2.8g,海藻糖40g、甘露醇60g。
制备方法:
(1)称取JRF103,二油酰磷脂酰乙醇胺,DEPE-PEG3400,胆固醇置于无水乙醇中,在50℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入50℃的注射用水中,搅拌水化,得脂质体溶液粗品,减压浓缩去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行均质,均质压力1200bar,得脂质体溶液;
(3)称取冻干保护剂海藻糖和甘露醇,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
实施例12
按照以下方法制备JRF103脂质体冻干剂。
处方:JRF103 3.2g, 磷脂酰肌醇52g,胆固醇6.3 g,DSPE-PEG 3400 2.5g,海藻糖40g、蔗糖40g。
制备方法:
(1)称取JRF103,磷脂酰肌醇,DSPE-PEG3400,胆固醇置于无水乙醇中,在50℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入50℃的注射用水中,搅拌水化,得脂质体溶液粗品,减压浓缩去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行均质,均质压力1200bar,得脂质体溶液;
(3)称取冻干保护剂海藻糖和蔗糖,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
经测定,实施例8-12制得的冻干粉复溶后的平均粒径92.3~136.8nm,电位-41.2~-28.7,包封率均在85%以上。
Claims (7)
1.一种pan-HER抑制剂的药物组合物,所述药物组合物以式Ⅰ所示化合物或其药学上可接受的盐为活性药物,其特征在于,所述药物组合物由以下成分组成:
式Ⅰ化合物或其药学上可接受的盐0.1~0.4%w/v,
,
磷脂1~6%w/v,
胆固醇0.2~1%w/v,
聚乙二醇或聚乙二醇化磷脂0.1~0.5%w/v,
冻干保护剂5~20% w/v,
余量为注射用水;
所述磷脂选自大豆磷脂、蛋黄卵磷脂、氢化大豆卵磷脂、磷脂酰甘油、二油酰磷脂酰乙醇胺、磷脂酰肌醇中的一种;
所述冻干保护剂选自蔗糖、海藻糖、甘露醇中的一种,或海藻糖和甘露醇的组合,或海藻糖和蔗糖的组合;
所述聚乙二醇为聚乙二醇2000;
所述聚乙二醇化磷脂选自二芥酰基磷脂乙醇胺-聚乙二醇、二硬脂酰磷脂乙醇胺-聚乙二醇、胆固醇-聚乙二醇、 二硬脂酰基磷脂酰胆碱-聚乙二醇、磷脂酰乙醇胺-聚乙二醇、磷脂酰胆碱-聚乙二醇中的一种;
所述药物组合物中药脂比为1:6~14 w/w,磷脂和胆固醇比为4~8:1w/w。
2.根据权利要求1所述的药物组合物,其特征在于,所述聚乙二醇化磷脂选自二芥酰基磷脂乙醇胺-聚乙二醇或二硬脂酰磷脂乙醇胺-聚乙二醇。
3.根据权利要求1所述的药物组合物,其特征在于,所述聚乙二醇化磷脂中,其聚乙二醇的分子量为800~20000 Da。
4.根据权利要求1-3任一项所述的药物组合物的制备方法,其特征在于,包括如下步骤:
(1)称取活性药物,磷脂,聚乙二醇或聚乙二醇化磷脂,胆固醇置于有机溶媒中,在40~60℃条件下加热搅拌溶解,得有机相;
(2)在搅拌状态下,将有机相注入40~60℃的注射用水中,搅拌水化,得脂质体溶液粗品,去除脂质体溶液粗品中有机溶媒,并对脂质体溶液粗品进行整粒,得脂质体溶液;
(3)称取冻干保护剂,用注射用水溶解后加入脂质体溶液,并用注射用水定容至处方量,搅拌混匀,过滤除菌,分装,冻干,压盖,即得。
5.根据权利要求4所述的制备方法,其特征在于,所述步骤(1)有机溶媒选自无水乙醇、无水***、氯仿和甲醇中的一种或两种。
6.根据权利要求4所述的制备方法,其特征在于,所述步骤(2)去除脂质体溶液粗品中有机溶媒的方法为超滤或减压浓缩。
7.根据权利要求4所述的制备方法,其特征在于,所述步骤(2)整粒的方法为挤出法或均质法。
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Denomination of invention: A pharmaceutical composition of pan HER inhibitors and its preparation method Granted publication date: 20231121 Pledgee: Industrial Bank Limited by Share Ltd. Chengdu branch Pledgor: Chengdu Jinrui Jiye Bio-Technology Co.,Ltd. Registration number: Y2024980008616 |