CN116421705A - 降低宫颈癌发病风险的药物制剂 - Google Patents
降低宫颈癌发病风险的药物制剂 Download PDFInfo
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- CN116421705A CN116421705A CN202310166260.5A CN202310166260A CN116421705A CN 116421705 A CN116421705 A CN 116421705A CN 202310166260 A CN202310166260 A CN 202310166260A CN 116421705 A CN116421705 A CN 116421705A
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Abstract
本发明公开了一种降低宫颈癌发病风险的药物制剂及其制备方法,所述药物制剂由卡波姆、聚卡波菲、黑树莓提取物、酸化乳球蛋白、甘油、依地酸钠、苯氧乙醇、纯化水和三乙醇胺组成。通过与含缓冲液的聚合物溶胶混合加入磁性纳米粒子作用于预防处发生凝胶,而通过外界高频交变磁场对人体局部的作用实现可控的溶胶释放药物,达到根据体内病毒浓度曲线而针对性释放相对药物,防止耐药性。本发明药物制剂中采用酸化乳球蛋白抑制HPV病毒感染正常细胞,联合黑树莓提取物清除活性氧堆积,抑制细胞癌变风险,达到降低宫颈癌发病风险的目的。
Description
技术领域
本发明属于医药技术领域,具体涉及一种降低宫颈癌发病风险的药物制剂。
背景技术
宫颈癌(cervical carcinoma)是女性生殖系统的常见恶性肿瘤,发生在阴道部和宫颈管,在全球妇科肿瘤中仅次于乳腺癌位居第二。宫颈癌的病因目前尚未明确,大量流行病学资料和研究认为,感染人乳头瘤状病毒(human papilloma virus,HPV),尤其是高危型HPV感染(HPV16,HPV18)是主要危险因素。但并不是所有的HPV感染者都会发展成为宫颈癌,还应考虑其他因素,例如性生活紊乱、营养不良等。近年来很多研究报道指出宫颈癌和微量营养素有关,已经被证实具有预防人类恶性肿瘤作用的营养素包括维生素C、维生素E、原青花素、白藜芦醇等,事实上这些均具有很好的抗过氧化作用。在宫颈癌发生过程中,机体内活性氧浓度的增加会造成DNA以及蛋白的损伤,最终促进癌变。抗氧化物质可使活性氧失去活性,防止氧化损伤,从而降低宫颈癌发生的几率,达到预防宫颈癌的目的。
人乳头瘤病毒HPV以人作为唯一宿主,感染人体皮肤组织和黏膜组织的上皮细胞,尤其集中在口腔、手脚和男女生殖器等部位。病毒与细胞的直接接触是HPV感染宿主必要的先决条件,当皮肤或黏膜表层的物理组织保护受损,导致组织细胞暴露于游离的成熟病毒,病毒就有机会通过这种上皮细胞的微创伤侵犯并进入细胞,这通常被认为是病毒生命周期的开始阶段,也是预防的最佳阶段。同样,当病毒成熟后也会从细胞中释放,从而感染新的细胞,在口腔、手脚及男女生殖器处造成更多的感染及病变,最后导致病情的扩大、恶化及最后免疫系统无法清除形成尖锐湿疣、宫颈糜烂、慢性宫颈炎甚至肿瘤,对于已经宫颈癌的发病区域控制细胞组织的正常生理功能,减少活性氧堆积造成的DNA和蛋白损伤,可以达到预防宫颈癌的发病几率。目前,在国际上能有效预防HPV病毒感染的药物是默沙东公司HPV4价疫苗和葛兰素史克公司的二价疫苗”,主要还是预防型的疫苗,临床证实HPV的疫苗几乎能100%地预防一些HPV病毒株的感染,但是它并不能预防所有类型病毒株的感染,但是国内人群限制只适用于9-25岁,并且价格高昂。而在治疗上由于没有特效药因而采用的免疫调节药物,由于普遍存在无法有效地预防HPV感染、疗效不明确、价格昂贵等方面的缺陷而大大限制了其在临床上的使用。
此外,通过内服或内贴作用实现治疗无法保证在合适的时间内针对特定浓度的病毒进行作用,从而盲目地大量释放药物作用于换不,极有可能缩短达到耐药性的时间。因此如何考虑药物恰当地缓释,以及如何如何控制这种缓释作用,成为精确治疗的头等问题。
发明内容
本发明的目的是解决现有药物制剂无法有效地预防人乳头瘤状病毒感染、疗效不明确、价格昂贵的缺点,提供一种降低宫颈癌发病风险的药物制剂,本发明药物制剂中采用酸化乳球蛋白控制HPV病毒感染正常细胞、同时联合黑树莓提取物清除活性氧堆积,抑制癌变细胞生长,达到预防宫颈癌的目的。其基于根据外界交变磁场作用于人体内含词性纳米颗粒的凝胶而产热从而遥控溶胶释放药物,当撤去外界磁场后再次凝胶的原理实现药物可控地释放。
根据本发明的第一个方面,本发明提供了一种降低宫颈癌发病风险的药物制剂,所述药物制剂的pH为4.5-6.5,所述药物制剂由第一药物溶液、pH调节剂先混合、第二药物溶液和磁性纳米颗粒再依次加入所述先混合的混合物中而形成;所述pH调节剂为三乙醇胺;所述第一药物溶液由卡波姆、聚卡波菲、黑树莓提取物、酸化乳球蛋白、甘油、依地酸钠、苯氧乙醇和纯化水组成;
所述第二药物溶液包括泊洛沙姆、PBS缓冲液;所述磁性纳米颗粒由0.1-0.4%PVP包覆的四氧化三铁纳米颗粒所组成,优选地,粒径为28-35nm。
优选地,所述泊洛沙姆为泊洛沙姆127、泊洛沙姆188或泊洛沙姆407。
本发明药物制剂中所述酸化乳球蛋白用重组人血白蛋白代替;所述黑树莓提取物用桑葚提取物代替;所述卡波姆和聚卡波菲用羧丙基甲基纤维素代替。
优选的,所述药物溶液按重量百分比计算由以下成分组成:
卡波姆1%wt-3%wt,聚卡波菲1%wt-3%wt,黑树莓提取物1%wt-10%wt,甘油1%wt-3%wt,依地酸钠0.05%wt-0.1%wt,苯氧乙醇0.5%wt-1%wt,余量为纯化水和酸化乳球蛋白,所述酸化乳球蛋白在药物溶液中的浓度为100-600μg/ml。
优选的,所述酸化乳球蛋白由以下方法制备:
首先使用磷酸盐缓冲液溶解乳球蛋白20g,加入3-羟基-邻苯二甲酸酐溶液20g,搅拌2-4小时得混合液;
然后使用G25脱盐柱,使用磷酸盐缓冲溶液作为流动相对混合液进行脱盐处理;收集目标蛋白峰,使用超滤浓缩除菌过滤,可得酸化乳球蛋白。
酸化乳球蛋白经过酸酐修饰,其中碱性氨基酸赖氨酸、精氨酸被修饰,使蛋白整体等电点PI下降,呈现酸性。酸化的蛋白氨基酸序列N端携带正电荷与人乳头瘤病毒HPV L1C端负电区域结合,从而阻断人乳头瘤病毒HPV进入细胞,被结合的病毒可伴随凝胶体系被排除体外。
优选的,所述黑树莓提取物由以下方法制备:
1)以新鲜的黑树莓果实为原料,去除杂物并浸泡清洗;
2)降温到-20℃将果实打碎,冷冻干燥机冻干18-24h,出箱粉碎;
3)使用乙醇水溶液(60%v)溶解0-10℃下浸提,滤布过滤,低温减压蒸馏、浓缩、烘干后密封避光保存得黑树莓提取物。
黑树莓提取物常用的提取方式因温度和光照对活性影响较高,为解决以上问题本发明采用低温冷冻浸提的方法,可以很好的保留物质的活性。
黑树莓(Black raspberry)提取物中含有丰富的抗氧化活性物质,例如花青素、黄酮醇、白藜芦醇、鞣花丹宁和丹宁酸。检测发现黑树莓中抗氧化物质含量数倍于常见品种含量。其较强的抗氧化性能和免疫细胞调节功能可以清楚阴道上皮细胞的活性氧堆积,减少细胞DNA以及蛋白表达的癌变。同时实验证明一定浓度剂量下还可以抑制肿瘤细胞的生长,达到预防和治疗的效果。
根据本发明的另一个方面,本发明提供了一种基于交变磁场遥控缓释的降低宫颈癌发病风险的药物制剂的制备方法,包括以下步骤:
1)将卡波姆、聚卡波菲采用纯化水溶胀后待用;
2)甘油和纯化水组成的水溶液溶解黑树莓提取物、酸化乳球蛋白和依地酸钠,搅拌均匀得混合液;
3)将步骤1)和步骤2)所得溶液在常温下按比例混匀,然后加入苯氧乙醇搅拌均匀得第一药物溶液;
4)使用三乙醇胺调节药物溶液pH=4.5-6.5;
5)将泊洛沙姆溶解于pH=4.5-6.5的PBS缓冲液,使得两者质量比为1:1-35,混合均匀后,加入占混合物质量百分比为1.1-2.8%的磁性纳米颗粒,再次混合而制得。
本发明的第三个方面,是提供一种药物制剂组合物,其特征在于包括了上述的一种基于交变磁场遥控缓释的降低宫颈癌发病风险的药物制剂,以及一种基于交变磁场遥控缓释的宫颈消炎制剂,其中所述消炎制剂包括:消炎成分,第二药物溶液和磁性纳米颗粒,
所述消炎成分包括甲硝唑、左氧氟沙星、阿奇霉素、阿莫西林任一者或其组合,或者包括中药成分,包括冬青油、蛇床子油、丁香罗勤油、苦参、益母草、百部、红花、黄柏、千里光、薄荷脑、冰片,
所述消炎制剂的制备方法包括:
(1’)将泊洛沙姆溶解于pH=4.5-6.5的PBS缓冲液,使得两者质量比为1:1-35,混合均匀,形成第二药物溶液;
(2’)向步骤(1’)中混合均匀的第二药物溶液中依次加入所述消炎成分,以及占第二药物溶液质量百分比为1.6-2.0%的磁性纳米颗粒,再次混合而制得。
所述磁性纳米颗粒由0.1-0.4%PVP包覆的四氧化三铁纳米颗粒所组成,优选地,粒径为28-35nm。
本发明所述的降低宫颈癌发病风险的制剂可制备成凝胶制剂适用于阴道外用凝胶,在阴道内黏膜形成有效的剂量浓度,直接作用于阴道黏膜细胞,预防HPV病毒感染和扩散,清除组织的活性氧堆积的细胞,抑制宫颈癌细胞生长,达到预防宫颈癌的作用,外用优势在于局部物质浓度大大优于口服和注射,对细胞癌变实现预防和治疗的效果。
本发明所述的降低宫颈癌发病风险制剂,可用于预防和/或治疗女性宫颈癌。
本发明机理为:在外界交变磁场作用下,凝胶中磁性纳米颗粒产热使得凝胶溶胶,释放出第一药物溶液和/或药物制剂组合物中的成分,由此1)在病毒入侵靶细胞的第一阶段,酸化的蛋白质表面带大量正电荷与人乳头瘤病毒HPV L1C端负电区域结合,从而阻断人乳头瘤病毒HPV进入细胞,被结合的病毒伴随凝胶体系被排除体外;2)黑树莓提取物中含有丰富的抗氧化活性物质,例如花青素、VC、VE等,通过冷冻浸提的方法可以很好的保留抗氧化物质的活性,通过外用凝胶形式在阴道局部形成有效的剂量浓度,直接作用于活性氧堆积的组织细胞,平衡自由氧堆积引起的异常细胞生长环境,减少细胞癌变风险,黑树莓中的复杂多糖成分可以形成阻断病毒颗粒感染细胞的糖蛋白粘接通道,减少病毒对正常细胞的感染。外用优势在于凝胶体系的优良的吸附粘度可形成局部有效物质高浓度作用,优于口服。
本发明降低宫颈癌发病风险的药物制剂具有阻断HPV病毒入侵细胞、阻止活性氧对细胞DNA损伤保持正常的细胞功能、安全无毒副作用、成本低廉等显著优势,临床易于推广。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明了,下面结合具体实施方式,对本发明进一步详细说明。应该理解,这些描述只是示例性的,而并非要限制本发明的范围。
实施例1
酸化乳球蛋白方法如下:pH8.4的PBS缓冲液以50倍体积溶解乳球蛋白20g,加入3-羟基-邻苯二甲酸酐溶液20g,搅拌2-4小时,使用G25脱盐柱,使用PBS作为流动相,收集蛋白峰,后使用超滤浓缩除菌过滤,可得酸化乳球蛋白。
黑树莓提取物制备方法如下:以新鲜的黑树莓果实为原料,去除杂物并浸泡清洗;降温到-30℃将果实打碎,冷冻干燥机冻干18-24h,出箱粉碎使用乙醇水溶液(60%v)溶解,0-10℃下浸提,滤布过滤,低温减压蒸馏浓缩烘干后密封避光保存。
阻断人乳头瘤病毒传染途径的药物制剂的制备方法,包含以下步骤:
1)将卡波姆和聚卡波菲采用纯化水溶胀后待用;
2)甘油和纯化水组成的水溶液溶解黑树莓提取物和酸化乳球蛋白、依地酸钠,搅拌均匀得混合液;
3)将步骤1)和步骤2)所得溶液在常温下按比例混匀,然后加入苯氧乙醇搅拌均匀得第一药物溶液;
4)使用三乙醇胺调节药物溶液pH=4.5-6.5;
5)将泊洛沙姆溶解于pH=4.5-6.5的PBS缓冲液,使得两者质量比为1:1-35,混合均匀后,加入占混合物质量百分比为1.1-2.8%的磁性纳米颗粒,再次混合而制得。
凝胶灌装到妇科装用推注管中,氮气保护下封口,完成外用制剂的制备。
其中
实施例2
酸化乳球蛋白和黑树莓提取物的制备方法同实施例1,区别在于药物溶液中各物质的重量百分比,本实施例药物溶液中各物质的重量百分比如下:
将凝胶灌装到妇科装用推注管中,氮气保护下封口,完成外用制剂的制备。
实施例3
药物制剂组合物的制备方法,将实施例1或2的药物制剂制备完毕后,再制备所述消炎制剂的包括:
(1)将泊洛沙姆溶解于pH=5.2的PBS缓冲液,使得两者质量比为1:25,混合均匀,形成第二药物溶液;
(2)向步骤(1)中混合均匀的第二药物溶液中依次加入甲硝唑,以及占第二药物溶液质量百分比为1.7%的磁性纳米颗粒,再次混合而制得,其中所述磁性纳米颗粒由0.3%PVP包覆的四氧化三铁纳米颗粒所组成,粒径为29-32nm。
实施例4
本实施例例举一种实施例1和2药物制剂的人工智能缓释治疗辅助穿戴式结构,包括,穿戴件,交变磁场发生与控制器,其中,所述穿戴件包括裤形穿戴件主体,设置在所述裤形穿戴件主体夹层内的与所述交变磁场发生与控制器电连接的产磁部件,所述产磁部件包括埋设于所述裤形穿戴件主体裆部夹层内的两条被金属线圈缠绕的不锈钢弧形条,分别从每一弧形条两侧延伸出的含有磁性纳米颗粒的水凝胶条,和所述水凝胶条延伸末端的导磁片,其中,
所述弧形条外表通过热缩封与柔性导磁条的一端连接密封以绝缘,所述水凝胶条、导磁片,以及热缩封都在所述裤形穿戴件主体的内面和外面之间的夹层内。
所述穿戴式人工智能缓释治疗仪还包括可佩带所述交变磁场发生与控制器的腰带,用于便携,所述交变磁场发生与控制器可与用户智能终端通讯,实现交变磁场产生的参数设置,药物缓释曲线设置,所述交变磁场发生与控制器通过设定好的参数和曲线对所述弧形条发出高频脉冲电流,从而在所述裆部处产生交变磁场,通过导磁条将磁场约束引导至导磁片而从弧形条另一个端延伸的柔性导磁条延伸末端的导磁片中进入,形成交变环形磁场,作用于宫颈口施加而凝胶的所述药物制剂,从而使得其中的纳米颗粒不断产热而使得凝胶溶胶释放出第一药物溶液中的所有成分,当停止发出高频脉冲电流后溶胶再次凝胶。所述交变磁场发生与控制器根据设置的所述药物缓释曲线而进行高频脉冲电流的发出和停止,以实现在规定的时段内释放特定剂量的药物,达到遥控缓释,针对性预防或治疗的目的。
其中智能终端中设有自然语言识别程序,能够根据扫描的病例和每个所述预设时间检测到的病毒或细菌分析报告和宫颈病理切片报告而综合识别出病情,从而自动选择相应药物缓释曲线命令所述交变磁场发生与控制器进行工作。
实施例5
为了进一步证明本发明所述凝胶的疗效,申请人进行了以下临床试验验证。
使用本发明的凝胶(实施例1或2制备所得)用于治疗HPV病毒感染阳性反复感染患者做了初步试用观察,结果表明,该凝胶治疗HPV病毒阳性治疗有效,无任何刺激和不良反应。
高危HPV16、18感染者5例,使用抗HPV病毒凝胶敷料3个月后阳性病毒均转阴,具体结果见表1,高于文献报道(《Microbes&Infection》,2016,18(2):148,A randomized open-label clinical trial of an anti-HPV biological dressing(JB01-BD)administeredintravaginally to treat high-risk HPV infection)酸酐修饰乳球蛋白敷料对高危HPV病毒转阴率60.5%。在阻断HPV病毒颗粒感染过程中,酸化乳球蛋白可以吸附病毒颗粒后随排除体内,黑树莓提取物中的多糖结构可以封闭细胞表面的糖蛋白结合位点,阻断病毒进入细胞内的通道。黑树莓提取物中花青素等成分中和氧自由基同时还对变异细胞有一定抑制作用。
采用本发明制备凝胶,病例选择为HPV高危病毒阳性患者5例,使用期3个月,PCR检测HPV病毒E6、E7mRNA。
表1测试病例治疗后病毒检测变化
序号性别年龄首次病程记录再次病程记录用药周期1女37HPV-18阳性HPV-18阴性25支,3个月2女37HPV-16阳性HPV-16阴性25支,3个月3女38HPV-16阳性HPV-16阴性25支,3个月4女42HPV-18阳性HPV-18阴性25支,3个月5女35HPV-16阳性HPV-16阴性25支,3个月
尽管已经详细描述了本发明的实施方式,但是应该理解的是,在不偏离本发明的精神和范围的情况下,可以对本发明的实施方式做出各种改变、替换和变更。
Claims (9)
1.一种降低宫颈癌发病风险的药物制剂,其特征在于,所述药物制剂的pH为4.5-6.5,所述药物制剂由第一药物溶液、pH调节剂先混合、第二药物溶液和磁性纳米颗粒再依次加入所述先混合的混合物中而形成;所述pH调节剂为三乙醇胺;所述第一药物溶液由卡波姆、聚卡波菲、黑树莓提取物、酸化乳球蛋白、甘油、依地酸钠、苯氧乙醇和纯化水组成;
所述第二药物溶液包括泊洛沙姆、PBS缓冲液;所述磁性纳米颗粒由0.1-0.4%PVP包覆的四氧化三铁纳米颗粒所组成,粒径为28-35nm。
2.根据权利要求1所述的药物制剂,其特征在于:所述药物溶液按重量百分比计算由以下成分组成:卡波姆1%wt-3%wt,聚卡波菲1%wt-3%wt,黑树莓提取物1%wt-10%wt,甘油1%wt-3%wt,依地酸钠0.05%wt-0.1%wt,苯氧乙醇0.5%wt-1%wt,余量为纯化水和酸化乳球蛋白,所述酸化乳球蛋白在药物溶液中的浓度为100-600μg/ml;四氧化三铁纳米颗粒粒径为28-35nm;所述泊洛沙姆为泊洛沙姆127、泊洛沙姆188或泊洛沙姆407。
3.根据权利要求1所述的药物制剂,其特征在于:所述酸化乳球蛋白由以下方法制备:首先使用磷酸盐缓冲液溶解乳球蛋白,加入3-羟基-邻苯二甲酸酐溶液,搅拌2-4小时得混合液;然后使用G25脱盐柱,使用磷酸盐缓冲溶液作为流动相对混合液进行脱盐处理;收集乳球蛋白峰,使用超滤浓缩除菌过滤,可得酸化乳球蛋白。
4.根据权利要求1所述的药物制剂,其特征在于:所述黑树莓提取物由以下方法制备:1)以新鲜的黑树莓果实为原料,去除杂物并浸泡清洗;2)降温将果实打碎,冷冻干燥机冻干,出箱粉碎;3)使用乙醇水溶液溶解,0-10℃下浸提,使用滤布过滤后,低温减压蒸馏浓缩,烘干后密封避光保存得黑树莓提取物。
5.一种权利要求1-4任一项所述的药物制剂,其特征在于:所述酸化乳球蛋白用重组人血白蛋白代替;所述黑树莓提取物用桑葚提取物代替;所述卡波姆和聚卡波菲用羧丙基甲基纤维素代替。
6.一种权利要求1-5任一项所述药物制剂的制备方法:
1)将卡波姆、聚卡波菲采用纯化水溶胀后待用;
2)甘油和纯化水组成的水溶液溶解黑树莓提取物、酸化乳球蛋白和依地酸钠,搅拌均匀得混合液;
3)将步骤1)和步骤2)所得溶液在常温下按比例混匀,然后加入苯氧乙醇搅拌均匀得第一药物溶液;
4)使用三乙醇胺调节药物溶液pH=4.5-6.5;
5)将泊洛沙姆溶解于pH=4.5-6.5的PBS缓冲液,使得两者质量比为1:1-35,混合均匀后,加入占混合物质量百分比为1.1-2.8%的磁性纳米颗粒,再次混合而制得。
7.一种药物制剂组合物,其特征在于,包括了如权利要求1-6中任一项所述的基于交变磁场遥控缓释的降低宫颈癌发病风险的药物制剂,以及一种基于交变磁场遥控缓释的宫颈消炎制剂,其中,所述消炎制剂包括:消炎成分,第二药物溶液和磁性纳米颗粒,
所述消炎成分包括甲硝唑、左氧氟沙星、阿奇霉素、阿莫西林任一者或其组合,或者包括中药成分,包括冬青油、蛇床子油、丁香罗勤油、苦参、益母草、百部、红花、黄柏、千里光、薄荷脑、冰片,
所述消炎制剂的制备方法包括:
(1’)将泊洛沙姆溶解于pH=4.5-6.5的PBS缓冲液,使得两者质量比为1:1-35,混合均匀,形成第二药物溶液;
(2’)向步骤(1’)中混合均匀的第二药物溶液中依次加入所述消炎成分,以及占第二药物溶液质量百分比为1.6-2.0%的磁性纳米颗粒,再次混合而制得,其中所述磁性纳米颗粒由0.1-0.4%PVP包覆的四氧化三铁纳米颗粒所组成,粒径为28-35nm。
8.一种权利要求1-5任一项所述药物制剂的用途,其特征在于:所述药物制剂在制备降低女性宫颈癌发病风险药物中的应用。
9.一种权利要求7所述药物制剂组合物,其特征在于:所述药物制剂组合物在制备降低女性宫颈癌发病风险药物中的应用。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1200300A (zh) * | 1997-05-27 | 1998-12-02 | 刘道矩 | 颈脑通低频电子脉冲治疗仪 |
CN1703233A (zh) * | 2002-07-12 | 2005-11-30 | 米德列斯公司 | 防止蛋白氧化降解的方法和组合物 |
CN101475224A (zh) * | 2009-01-22 | 2009-07-08 | 浙江大学 | 聚乙烯吡咯烷酮修饰超顺磁性纳米氧化铁的制备法及用途 |
CN103529023A (zh) * | 2013-10-11 | 2014-01-22 | 东南大学 | 一种端粒酶活性检测方法 |
CN103979612A (zh) * | 2014-05-23 | 2014-08-13 | 苏州大学 | 一种制备四氧化三铁纳米粒子的方法 |
CN108785656A (zh) * | 2017-10-10 | 2018-11-13 | 迈迪速能医学技术(天津)有限公司 | 一种降低宫颈癌发病风险的药物制剂及其制备方法 |
CN113143883A (zh) * | 2021-02-01 | 2021-07-23 | 西北大学 | 一种磁控释药系统 |
CN115245563A (zh) * | 2022-01-05 | 2022-10-28 | 郑州大学第一附属医院 | 一种用于抑制肿瘤细胞的m6A去甲基化酶FTO磁性颗粒的制备装置及方法 |
-
2023
- 2023-02-27 CN CN202310166260.5A patent/CN116421705A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1200300A (zh) * | 1997-05-27 | 1998-12-02 | 刘道矩 | 颈脑通低频电子脉冲治疗仪 |
CN1703233A (zh) * | 2002-07-12 | 2005-11-30 | 米德列斯公司 | 防止蛋白氧化降解的方法和组合物 |
CN101475224A (zh) * | 2009-01-22 | 2009-07-08 | 浙江大学 | 聚乙烯吡咯烷酮修饰超顺磁性纳米氧化铁的制备法及用途 |
CN103529023A (zh) * | 2013-10-11 | 2014-01-22 | 东南大学 | 一种端粒酶活性检测方法 |
CN103979612A (zh) * | 2014-05-23 | 2014-08-13 | 苏州大学 | 一种制备四氧化三铁纳米粒子的方法 |
CN108785656A (zh) * | 2017-10-10 | 2018-11-13 | 迈迪速能医学技术(天津)有限公司 | 一种降低宫颈癌发病风险的药物制剂及其制备方法 |
CN113143883A (zh) * | 2021-02-01 | 2021-07-23 | 西北大学 | 一种磁控释药系统 |
CN115245563A (zh) * | 2022-01-05 | 2022-10-28 | 郑州大学第一附属医院 | 一种用于抑制肿瘤细胞的m6A去甲基化酶FTO磁性颗粒的制备装置及方法 |
Non-Patent Citations (1)
Title |
---|
张倩文等: "《电子元器件详解实用手册》", 北京:中国铁道出版社有限公司, pages: 133 - 134 * |
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