CN115227651A - 一种聚多巴胺修饰的丹曲林盐纳米粒及其制备方法 - Google Patents
一种聚多巴胺修饰的丹曲林盐纳米粒及其制备方法 Download PDFInfo
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- CN115227651A CN115227651A CN202110466380.8A CN202110466380A CN115227651A CN 115227651 A CN115227651 A CN 115227651A CN 202110466380 A CN202110466380 A CN 202110466380A CN 115227651 A CN115227651 A CN 115227651A
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- pharmaceutically acceptable
- dantrolene
- acceptable salt
- polydopamine
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Abstract
本发明公开了一种聚多巴胺修饰的丹曲林盐纳米粒及其制备方法。本发明提供的聚多巴胺修饰的纳米粒的制备方法包括如下步骤:在pH=8~10下,将水、多巴胺或其药学上可接受的盐和丹曲林或其药学上可接受的盐混匀得聚多巴胺修饰的纳米粒即可。本发明的制备方法操作简单,反应条件温和,无需高温,并且不含有机溶剂,安全环保,所需原料易获得,且制得的纳米粒形态均一。此外,制得的聚多巴胺修饰的纳米粒加水复溶后的pH值约为7,更接近血浆的pH值,具有良好的生物相容性,并且具有良好的缓释效果。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种聚多巴胺修饰的丹曲林盐纳米粒及其制备方法。
背景技术
恶性高热是一种遗传性疾病,可由吸入麻醉药或去极化肌松药琥珀胆碱诱发。恶性高热易感者体内肌细胞中肌浆网的RYR 1(ryanodine-1,兰尼定受体-1)发生基因突变,在诱发药物的作用下,肌细胞内Ca2+浓度迅速增高,肌肉挛缩,产热急剧增加,体温迅速升高,同时产生大量乳酸和二氧化碳,出现酸中毒、低氧血症、高血钾、心律失常等一系列变化,严重者可致患者死亡。恶性高热在人群中的发病率低,但在没有特效药的情况下死亡率高。丹曲林钠(dantrolene sodium)通过与RYR 1结合,可降低细胞内Ca2+浓度,从而抑制骨骼肌兴奋-收缩耦联,是治疗恶性高热的特效药,用于预防及治疗恶性高热。
国外已有上市产品Intravenous和均为注射用冻干粉针剂。前者的规格是20mg/瓶,使用时需加入60mL水摇匀至澄清后使用,pH值为9.5,于1979年获FDA批准上市;后者规格为250mg/瓶,使用时仅需5mL无菌水稀释摇匀后使用,pH值为10.3,与第一代相比的配置时间大大缩短,降低了患者的并发症风险,于2014年获FDA批准上市。国内目前仅有丽珠集团仿制Intravenous的注射用丹曲林钠,该产品于2020年10月份取得国家药品监督管理局注册批件。
聚多巴胺(polydopamine,PDA)是由多巴胺单体经过氧化聚合而成的真黑素类物质,具有良好的生物粘附性和生物相容性,几乎可在任一固体表面形成复合层,并且制备过程简单温和,粒径可控,作为药物载体具有改善亲水性,二级反应性等优点。目前已有文献关于聚多巴胺在药物载体中的应用,例如负载阿霉素的多巴胺修饰的竹炭纳米粒子、负载阿霉素的聚多巴胺纳米颗粒、聚多巴胺修饰的载榄香烯介孔二氧化硅纳米粒等,但体外的药物释放率都较低,最高释放率分别为31.59%、24%、20.07%,并且缓释时间在30小时以内。
例如,文献1(刘箫,洪沙沙,张羱,等.多巴胺修饰的竹炭纳米粒子的合成及其光热控制药物释放的研究[J].山西大学学报(自然科学版),2020,v.43;No.167(01):149-154.)报道了多巴胺修饰的竹炭纳米粒子,在pH=5.4的缓冲溶液中用808nm近红外光(2.0W/cm2)激发,24h内药物的累积释放量达到38%。
文献2(刘宇炜,郭卓.聚多巴胺-阿霉素纳米颗粒对癌细胞的化疗-光热治疗协同作用[J].高等学校化学学报,2015,36(07):1389-1394.)报道了负载阿霉素的聚多巴胺纳米颗粒的药物在pH=5.0条件下药物的释放率达到24%,缓释时间在30小时以内。
文献3(盛晓丹,刘臻,罗砚曦,等.聚多巴胺修饰的载榄香烯介孔二氧化硅纳米粒的制备及其靶向抗肿瘤活性研究[J].中草药,2020,v.51;No.669(10):158-167.)聚多巴胺修饰的载榄香烯介孔二氧化硅纳米粒在pH=3.0释放介质中24小时累计释放约20.07%。
发明内容
本发明所要解决的技术问题在于现有的丹曲林钠的制剂生物相容性较差的问题,本发明提供了一种聚多巴胺修饰的丹曲林盐纳米粒及其制备方法,本发明的聚多巴胺修饰的丹曲林钠纳米粒复溶后更接近血浆的pH,降低了丹曲林钠的刺激性(也即提高了生物相容性),并且具有良好的缓释效果。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种聚多巴胺修饰的纳米粒的制备方法,其包括如下步骤:
在pH=8~10下,将水、多巴胺或其药学上可接受的盐和丹曲林或其药学上可接受的盐混匀得聚多巴胺修饰的纳米粒即可。
在所述的制备方法中,体系的pH可使用pH调节剂进行调节,所述的pH调节剂可为本领域常规的能将pH调节至8~10的试剂,优选碱金属的氢氧化物(例如氢氧化钠)、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾和盐酸中的一种或多种,更优选氢氧化钠和/或盐酸。
在所述的制备方法中,所述的pH优选为8.5~9.0。
在所述的制备方法中,多巴胺的药学上可接受的盐可为本领域常规的盐,例如盐酸盐、硫酸盐或磷酸盐,优选盐酸盐。
在所述的制备方法中,丹曲林的药学上可接受的盐可为本领域常规的盐,例如钠盐、钾盐或钙盐,优选钠盐。
在所述的制备方法中,所述的聚多巴胺修饰的纳米粒可为聚多巴胺修饰的丹曲林盐纳米粒,聚多巴胺修饰的丹曲林盐纳米粒中盐的种类本领域技术人员可以根据体系中的阳离子确定,例如若上述制备方法的体系中的阳离子除了少量多巴胺的阳离子、丹曲林钠的阳离子和H+离子外,其它阳离子为Na+,可以确定该制备方法得到的聚多巴胺修饰的纳米粒为聚多巴胺修饰的丹曲林钠,所述的聚多巴胺修饰的丹曲林盐纳米粒优选聚多巴胺修饰的丹曲林钠纳米粒。
在所述的制备方法中,所述的丹曲林或其药学上可接受的盐的平均粒径优选为50~300nm,更优选200~300nm,例如230.9nm或230nm。
在所述的制备方法中,所述的丹曲林或其药学上可接受的盐优选为研磨后的丹曲林或其药学上可接受的盐,研磨时使用的研磨珠的直径优选为0.1mm~1.0mm,更优选0.2mm~0.5mm,研磨时的转速优选1000rpm~4000rpm(例如2500rpm),研磨时间优选20~60分钟(例如30分钟)。
在所述的制备方法中,所述的丹曲林或其药学上可接受的盐与水的质量体积比可为0.1~3mg/mL,优选0.4~1mg/mL。
在所述的制备方法中,所述的多巴胺或其药学上可接受的盐与水的质量体积比可为0.1~5mg/mL,优选0.5~2mg/mL,更优选0.8~1.5mg/mL。
在所述的制备方法中,所述的“丹曲林或其药学上可接受的盐”与所述的“多巴胺或其药学上可接受的盐”的质量比可为1:1~1:5,优选1:2~1:4。
在所述的制备方法中,所述的混匀可包含超声和搅拌步骤,超声时间优选3~40分钟,更优选5~20分钟;搅拌时间优选15~40小时,更优选24~35小时,搅拌温度可为0~40℃,优选10~30℃(例如25℃)。
在所述的制备方法中,得到聚多巴胺修饰的纳米粒后,可进一步包含后处理,其包括如下步骤:分离(例如离心或过滤)后干燥得聚多巴胺修饰的纳米粒;或分离(例如离心或过滤)后,加水和冻干保护剂,再冻干得聚多巴胺修饰的纳米粒冻干粉;所述的冻干保护剂可为蔗糖、海藻糖和甘露醇中的一种或多种,优选蔗糖和/或甘露醇,更优选蔗糖;上述加入的冻干保护剂与水的质量体积比可为0.01g/mL~0.1g/mL,优选0.025g/mL~0.075g/mL,更优选0.025g/mL~0.04g/mL,所述的丹曲林或其药学上可接受的盐与后处理中加入的水的质量体积比优选为10mg/mL~40mg/mL,更优选20mg/mL~30mg/mL,所述的丹曲林或其药学上可接受的盐与所述的冻干保护剂的质量比优选为1:1~1:4,优选1:2~1:3。
在某一实施方案中,所述的制备方法的原料仅包含所述的水、所述的多巴胺或其药学上可接受的盐、所述的pH调节剂和所述的丹曲林或其药学上可接受的盐。
本发明还提供了一种聚多巴胺修饰的纳米粒,其制备方法如上所述。所述的聚多巴胺修饰的纳米粒的平均粒径优选300~600nm,更优选400nm~500nm(例如433.5nm),所述的聚多巴胺修饰的纳米粒优选聚多巴胺修饰的丹曲林盐纳米粒,更优选为聚多巴胺修饰的丹曲林钠纳米粒;所述的聚多巴胺修饰的纳米粒优选为上述聚多巴胺修饰的纳米粒冻干粉,更优选聚多巴胺修饰的丹曲林盐纳米粒冻干粉,最优选聚多巴胺修饰的丹曲林钠纳米粒冻干粉。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“水”包含去离子水、无菌水和超纯水中的一种或多种,例如去离子水和/或超纯水。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明提供了一种聚多巴胺修饰的丹曲林盐纳米粒及其制备方法,本发明的聚多巴胺修饰的丹曲林盐纳米粒药物加水复溶后的pH值约为7,更接近血浆的pH值,具有良好的生物相容性,并且具有良好的缓释效果。且本发明的聚多巴胺修饰的丹曲林盐纳米粒的制备方法操作简单,反应条件温和,无需高温,并且不含有机溶剂,安全环保,所需原料易获得,且制得的纳米粒形态均一。
附图说明
图1是粒径分布图,其中左图是通过实施例1制备的丹曲林钠冻干粉的粒径分布图,右图是通过实施例2制备的聚多巴胺修饰的丹曲林钠冻干粉的粒径分布图。
图2是DSC图谱,其中DS.001是通过实施例1制备的丹曲林钠冻干粉,PDA.001是指通过实施例3制备的聚多巴胺冻干粉,DS-DA.001是指通过实施例2制备的聚多巴胺修饰的丹曲林钠冻干粉,PDA+DS.001是PDA.001与DS.001的物理混合物。
图3是扫描电镜图。其中3-1图是通过实施例1制备的丹曲林钠冻干粉的扫描电镜图,3-2图是通过实施例3制备的聚多巴胺冻干粉的扫描电镜图,3-3图是通过实施例2制备的聚多巴胺修饰的丹曲林钠冻干粉。
图4是溶出曲线图。其中曲线1是通过实施例2制备的聚多巴胺修饰的丹曲林钠冻干粉的溶出曲线,曲线2是通过实施例1制备的丹曲林钠冻干粉的溶出曲线,曲线3是丹曲林钠原料药的溶出曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本申请采用PSS公司的Nicomp 380ZLS粒度仪测定粒径和电位;通过动态光散射原理测定粒径,电泳光散射原理测量电位。
测定方法是将冻干粉溶于水配制成混悬液,根据仪器参数调节至合适的浓度(质量体积比在0.3-0.5mg/mL左右),将混悬液放入仪器中测定,得到粒径和电位结果。
实施例1
取5g丹曲林钠原料药(生产厂家:武汉赢元贝商贸有限公司)加入100mL水中制备50mg/mL的过饱和水溶液,超声20分钟,得到初步分散的丹曲林钠,之后采用研磨机进行研磨,选择转速为2500rpm,研磨时间为30分钟,研磨珠的直径为0.2mm,得到进一步分散的丹曲林钠,加水至体积为2mL,加入甘露醇(每1mL水中加入0.025g甘露醇)作为冻干保护剂,冻干后得到丹曲林钠冻干粉。
扫描电镜结果显示了丹曲林钠冻干粉的形状,参照说明书附图3中的图3-1。粒径测定结果显示了丹曲林钠冻干粉的尺寸,参照说明书附图1中左图,颗粒平均大小为230.9nm。
实施例2
一种聚多巴胺修饰的丹曲林钠纳米粒的制备方法,包括以下步骤:
取80mg盐酸多巴胺溶于100mL水中,加入NaOH溶液(0.1mol/L,1mL)调节pH至8.5,搅拌过程中加入40mg研磨后的丹曲林钠(采用研磨机研磨丹曲林钠原料药得到的,选择转速为2500rpm,研磨时间为30分钟,研磨珠的直径为0.2mm,颗粒平均大小为230nm),超声5分钟,25℃条件下搅拌24小时。搅拌结束后将溶液以10000rpm转速离心3次,向离心后的沉淀中加入去离子水,超声得到聚多巴胺修饰的丹曲林钠纳米粒的混悬液2mL,加入蔗糖(每1mL水加入0.04g蔗糖)作为冻干保护剂,冻干后得到聚多巴胺修饰的丹曲林钠纳米粒冻干粉。
扫描电镜结果显示了聚多巴胺修饰的丹曲林钠纳米粒冻干粉的形状,参照说明书附图3中的图3-3。粒径测定结果显示了聚多巴胺修饰的丹曲林钠纳米粒的尺寸,参照说明书附图1中右图,颗粒平均大小为433.5nm。
实施例3
将盐酸多巴胺溶于水中,加入NaOH调节pH至8.5,25℃条件下搅拌24小时。搅拌结束后将溶液以10000rpm转速离心3次,向沉淀中加入去离子水,超声得到聚多巴胺混悬液2mL,加入蔗糖(每1mL水加入0.04g蔗糖)作为冻干保护剂,冻干后得到聚多巴胺冻干粉。
扫描电镜结果显示了聚多巴胺冻干粉的形状,参照说明书附图3中的图3-2。由DSC图和扫描电镜图可以看出,聚多巴胺成功修饰到丹曲林钠的表面。参照说明书附图2和说明书附图3。
实施例4
对实施例1和实施例2制备的冻干粉以及丹曲林钠原料药进行体外的释放曲线考察。分别称取3份含有5mg丹曲林钠的冻干粉置于透析袋中,将装有冻干粉的透析袋放入60mL 50%丙二醇水溶液中,将以上溶液置于37℃,250rpm条件下震荡72小时,在设定的时间点取出1mL溶液,并补加1mL空白介质,采用高效液相色谱法对样品进行分析。
结果见说明书附图4,图中可以看出通过实施例1制备的丹曲林钠冻干粉的释放速率快于丹曲林钠原料药,与这两者相比,通过实施例2制备的聚多巴胺修饰的丹曲林钠冻干粉的释放速率更加均匀,并且呈现缓释效果。说明聚多巴胺修饰到丹曲林钠上可以达到缓释的效果。且实施例2制备的聚多巴胺修饰的丹曲林钠冻干粉的体外释放率可达到51.7%,并且缓释时间可达72h。
实施例5
取实施例2制备的冻干粉加水复溶,将实施例2制备的冻干粉以和水的质量体积比为1.5mg/mL(实际测得丹曲林钠在水中的浓度为0.5mg/mL)的比例加入水中,配制成混悬液,采用pH计测定其pH值为7.13。
取实施例1制备的冻干粉加水复溶,将实施例1制备的冻干粉以和水的质量体积比为0.7mg/mL(实际测得丹曲林钠在水中的浓度为0.5mg/mL)的比例加入水中,配制成混悬液,采用pH计测定其pH值为9.82。
取实施例3制备的冻干粉加水复溶,将实施例3制备的冻干粉以和水的质量体积比为0.5mg/mL,配制成混悬液,采用pH计测定其pH值为5.86。
Claims (10)
1.一种聚多巴胺修饰的纳米粒的制备方法,其特征在于,其包括如下步骤:
在pH=8~10下,将水、多巴胺或其药学上可接受的盐和丹曲林或其药学上可接受的盐混匀得聚多巴胺修饰的纳米粒即可。
2.如权利要求1所述的聚多巴胺修饰的纳米粒的制备方法,其特征在于:
在所述的制备方法中,体系的pH使用pH调节剂进行调节;
和/或,在所述的制备方法中,所述的pH为8.5~9.0;
和/或,在所述的制备方法中,多巴胺的药学上可接受的盐为盐酸盐、硫酸盐或磷酸盐;
和/或,在所述的制备方法中,丹曲林的药学上可接受的盐为钠盐、钾盐或钙盐;
和/或,在所述的制备方法中,所述的聚多巴胺修饰的纳米粒为聚多巴胺修饰的丹曲林盐纳米粒;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐的平均粒径为50~300nm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐与水的质量体积比为0.1~3mg/mL;
和/或,在所述的制备方法中,所述的多巴胺或其药学上可接受的盐与水的质量体积比为0.1~5mg/mL;
和/或,在所述的制备方法中,所述的“丹曲林或其药学上可接受的盐”与所述的“多巴胺或其药学上可接受的盐”的质量比为1:1~1:5;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤;
和/或,在所述的制备方法中,得到聚多巴胺修饰的纳米粒后,进一步包含后处理。
3.如权利要求2所述的聚多巴胺修饰的纳米粒的制备方法,其特征在于:
在所述的制备方法中,所述的pH调节剂为碱金属的氢氧化物、磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾和盐酸中的一种或多种;
和/或,在所述的制备方法中,多巴胺的药学上可接受的盐为盐酸盐;
和/或,在所述的制备方法中,丹曲林的药学上可接受的盐为钠盐;
和/或,在所述的制备方法中,所述的聚多巴胺修饰的纳米粒为聚多巴胺修饰的丹曲林钠纳米粒;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐的平均粒径为200~300nm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐,研磨时使用的研磨珠的直径为0.1mm~1.0mm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐,研磨时的转速为1000rpm~4000rpm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐,研磨时间为20~60分钟;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐与水的质量体积比为0.4~1mg/mL;
和/或,在所述的制备方法中,所述的多巴胺或其药学上可接受的盐与水的质量体积比为0.5~2mg/mL;
和/或,在所述的制备方法中,所述的“丹曲林或其药学上可接受的盐”与所述的“多巴胺或其药学上可接受的盐”的质量比为1:2~1:4;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤,超声时间为3~40分钟;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤,搅拌时间为15~40小时;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤,搅拌温度为0~40℃;
和/或,在所述的制备方法中,所述的后处理包括如下步骤:分离后干燥得聚多巴胺修饰的纳米粒;或分离后,加水和冻干保护剂,再冻干得聚多巴胺修饰的纳米粒冻干粉;
和/或,所述的制备方法的原料仅包含所述的水、所述的多巴胺或其药学上可接受的盐、所述的pH调节剂和所述的丹曲林或其药学上可接受的盐。
4.如权利要求3所述的聚多巴胺修饰的纳米粒的制备方法,其特征在于:
在所述的制备方法中,所述的pH调节剂为氢氧化钠和/或盐酸;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐的平均粒径为230.9nm或230nm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐,研磨时使用的研磨珠的直径为0.2mm~0.5mm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐,研磨时的转速为2500rpm;
和/或,在所述的制备方法中,所述的丹曲林或其药学上可接受的盐为研磨后的丹曲林或其药学上可接受的盐,研磨时间为30分钟;
和/或,在所述的制备方法中,所述的多巴胺或其药学上可接受的盐与水的质量体积比为0.8~1.5mg/mL;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤,超声时间为5~20分钟;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤,搅拌时间为24~35小时;
和/或,在所述的制备方法中,所述的混匀包含超声和搅拌步骤,搅拌温度为10~30℃;
和/或,在所述的后处理中,所述的分离为离心或过滤;
和/或,在所述的后处理中,所述的冻干保护剂为蔗糖、海藻糖和甘露醇中的一种或多种;
和/或,在所述的后处理中,所述的冻干保护剂与后处理中加入的水的质量体积比为0.01g/mL~0.1g/mL;
和/或,在所述的后处理中,所述的丹曲林或其药学上可接受的盐与后处理中加入的水的质量体积比为10mg/mL~40mg/mL;
和/或,在所述的后处理中,所述的丹曲林或其药学上可接受的盐与所述的冻干保护剂的质量比为1:1~1:4。
5.如权利要求4所述的聚多巴胺修饰的纳米粒的制备方法,其特征在于:
在所述的后处理中,所述的冻干保护剂为蔗糖和/或甘露醇;
和/或,在所述的后处理中,所述的冻干保护剂与后处理中加入的水的质量体积比为0.025g/mL~0.075g/mL;
和/或,在所述的后处理中,所述的丹曲林或其药学上可接受的盐与后处理中加入的水的质量体积比为20mg/mL~30mg/mL;
和/或,在所述的后处理中,所述的丹曲林或其药学上可接受的盐与所述的冻干保护剂的质量比为1:2~1:3。
6.如权利要求5所述的聚多巴胺修饰的纳米粒的制备方法,其特征在于:
在所述的后处理中,所述的冻干保护剂为蔗糖;
和/或,在所述的后处理中,所述的冻干保护剂与后处理中加入的水的质量体积比为0.025g/mL~0.04g/mL。
7.一种聚多巴胺修饰的纳米粒,其制备方法如权利要求1~6中任一项所述。
8.如权利要求7所述的聚多巴胺修饰的纳米粒,其特征在于,所述的聚多巴胺修饰的纳米粒的平均粒径为300~600nm;
和/或,所述的聚多巴胺修饰的纳米粒为聚多巴胺修饰的丹曲林盐纳米粒。
9.如权利要求8所述的聚多巴胺修饰的纳米粒,其特征在于,所述的聚多巴胺修饰的纳米粒的平均粒径为400nm~500nm;
和/或,所述的聚多巴胺修饰的纳米粒为聚多巴胺修饰的丹曲林钠纳米粒。
10.如权利要求7所述的聚多巴胺修饰的纳米粒,其特征在于,所述的聚多巴胺修饰的纳米粒的平均粒径为433.5nm;
和/或,所述的聚多巴胺修饰的纳米粒为进行如权利要求3所述的后处理后得到的聚多巴胺修饰的纳米粒冻干粉。
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CN117822310B (zh) * | 2024-03-05 | 2024-05-28 | 苏州金泉新材料股份有限公司 | 一种天然弱酸的具有抑菌效果的无刺激聚乳酸无纺布 |
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