CN115429773B - 一种制备药物纳米结晶制剂的方法 - Google Patents
一种制备药物纳米结晶制剂的方法 Download PDFInfo
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- CN115429773B CN115429773B CN202110614431.7A CN202110614431A CN115429773B CN 115429773 B CN115429773 B CN 115429773B CN 202110614431 A CN202110614431 A CN 202110614431A CN 115429773 B CN115429773 B CN 115429773B
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Abstract
本发明属于药物制剂领域，涉及一种制备药物纳米结晶制剂的方法。具体涉及一种在介质研磨制备过程中进行聚多巴胺包覆的药物纳米结晶制剂的制备方法。本发明避免了药物纳米结晶处方中常用的表面活性剂或亲水性高分子聚合物类稳定剂可能带来的安全性问题。本发明可方便地制备具有聚多巴胺包覆层的药物纳米结晶颗粒，聚多巴胺包被层既有利于药物纳米结晶的稳定性，还可共价修饰必要的功能基团，赋予药物纳米结晶特定功能。
Description
技术领域
本发明属于药物制剂领域，涉及一种制备药物纳米结晶制剂的方法。
背景技术
纳米结晶指的是纳米尺度(1-1000nm)的药物结晶颗粒，兼具高载药量和高分散度的优点，已被开发用于多种难溶性药物制剂的制备。为了保持纳米结晶的稳定，避免发生纳米结晶的长大和聚集，目前报道的药物纳米结晶多以表面活性剂和亲水性高分子聚合物为稳定剂，如聚维酮、吐温、泊洛沙姆和羟丙基甲基纤维素等，但这些物质用作药物辅料(特别是注射剂)时可能会存在安全性问题，不利于药物纳米结晶的临床应用。
多巴胺能在大部分固体表面附着并聚合，在固体表面形成聚多巴胺包覆膜。药物纳米结晶的表面亦可作为多巴胺附着的位点。聚多巴胺能与巯基或氨基反应形成共价键，为药物纳米结晶的功能化修饰提供了反应平台。
发明内容
本发明旨在提供一种包含聚多巴胺包覆层的药物纳米结晶及其制备方法。进一步的，本发明还提供通过聚多巴胺包覆层与含氨基或巯基衍生物的化学反应而进一步实现表面功能化修饰的药物纳米结晶。本发明的聚多巴胺包覆层是通过以球磨仪进行介质研磨制得的。
本发明所述药物结晶颗粒可以是分散在稳定剂水溶液中的混悬液，可以是通过冷冻干燥处理得到的冻干品，或者所述冻干品进一步分散在适宜的膏剂基质、膜剂基质或凝胶剂基质中。
本发明所述制剂可以用于静脉注射、局部注射、口服、阴道内、鼻腔内、口腔、直肠、眼内等粘膜途径给药，也可用于吸入给药或膀胱内灌注或手术切缘用药。
本发明的具体技术方案如下：
1)聚多巴胺包覆药物纳米结晶的制备：采用球磨仪实现，即将药物、多巴胺溶液和研磨珠置于研磨杯中，以球磨仪进行介质研磨制得。
2)聚多巴胺包覆药物纳米结晶的功能化修饰：通过聚多巴胺包覆药物纳米结晶与含氨基或巯基的功能化分子在水性溶液中反应4小时以上得到。
3)聚多巴胺包覆药物纳米结晶和聚多巴胺包覆药物纳米结晶制成制剂：可以直接分散在稳定剂水溶液中的混悬液；可以进一步加入适宜冷冻干燥保护剂后通过冷冻干燥处理得到的冻干品，临用前以适宜液体复溶至所需药物浓度；还可以进一步分散在适宜的膏剂基质、膜剂基质或凝胶剂基质中。
本发明中，所述药物可选自紫杉醇、多西他赛、冰片、细辛脑、醋酸棉酚、汉防己甲素、靛玉红、雷公藤甲素、熊果酸、非洛贝特、哌甲酯、吗替麦考酚酯、萘普生、奈韦拉平、硝苯地平、曲安西龙、奥氮平、奥美拉唑、奥沙普秦、非那吡啶、苯妥英钠等、甲噁唑、甲氧苄啶、利福平、卡马西平、布洛芬、吲哚美辛、氯吡格雷、氯雷他定、格列本脲、呋塞米、螺内酯、米非司酮、乙酰唑胺、氟哌啶醇、头孢呋辛酯、氢氯噻嗪、克拉霉素、卡巴他赛、喜树碱、9-羟基喜树碱、9-硝基喜树碱、9-氨基喜树碱、阿霉素、柔红霉素、阿柔比星、表阿霉素、伊达比星、戊柔比星、米托蒽醌、伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、尼洛替尼、拉帕替尼、帕唑帕尼、埃克替尼、凡德他尼、维罗非尼、克唑替尼、阿西替尼、伯舒替尼、卡博替尼、普纳替尼、瑞戈非尼、拉多替尼、达拉非尼、曲美替尼、阿法替尼、依鲁替尼、色瑞替尼、阿来替尼、阿帕替尼、尼达尼布、乐伐替尼、奥希替尼、奥莫替尼、长春碱、长春新碱、长春瑞滨、长春地辛、依维莫司、佐他莫司等。
本发明中，所述多巴胺水溶液含有浓度为0.01～1％(v/w)的多巴胺和总浓度在1～200mM的缓冲盐。
本发明中，所述的缓冲盐选自碳酸氢钠、枸橼酸钠-枸橼酸缓冲对或磷酸盐缓冲对。
本发明中，所述的药物和聚多巴胺的比例在20:1～1:1(w/w)。
本发明中，所述研磨珠尺寸可以选自0.1mm、0.2～0.3mm和1mm，材质选自二氧化锆或玛瑙。
本发明方法中，进一步包括将所述纳米结晶进行化学功能基团的修饰。
本发明中，所述化学功能基团选自聚乙二醇、透明质酸、壳聚糖及其衍生物。
本发明中，所述修饰为将药物纳米结晶与化学功能基团在水性溶液中反应4小时以上得到。
本发明中，所制得的药物纳米结晶制剂为混悬液、冻干品或冻干品分散剂；所述制剂可以用于静脉注射、局部注射、口服、阴道内、鼻腔内、口腔、直肠、眼内等粘膜途径给药，也可用于吸入给药或膀胱内灌注或手术切缘用药。
本发明的有益效果包括：
药物纳米结晶处方中采用了多巴胺，而不是常用的表面活性剂或亲水性高分子聚合物类稳定剂，从而避免了上述辅料成分可能带来的安全性问题；(2)药物纳米结晶表面的聚多巴胺包覆层有利于避免药物纳米结晶颗粒的聚集；(3)聚多巴胺包被层可共价修饰必要的功能基团，如可修饰聚乙二醇、透明质酸、壳聚糖及其衍生物，还可以修饰末端修饰了多肽或特定小分子。
附图说明
图1聚多巴胺包被多西他赛纳米结晶(左)和聚乙二醇修饰聚多巴胺包被多西他赛纳米结晶(右)粒径分布
图2聚乙二醇修饰聚多巴胺包被多西他赛纳米结晶4℃稳定性：(A)平均粒径随时间的变化；(B)第4天的粒径分布图；(C)第11天的粒径分布图；(D)第40天的粒径分布图。
具体实施方式
以下实施例是用来说明本发明的，不应被认为是以任何方式对本发明的限制。
实施例1聚多巴胺包被多西他赛纳米结晶
将100mg多西他赛混悬于30mL 4mg/mL NaHCO3水溶液中，置于研磨杯中，加入盐酸多巴胺22.5mg，加入60mL直径为1mm的95氧化锆珠，用行星式球磨仪以转速400rpm研磨4小时，即得，平均粒径约216.7nm。
实施例2聚乙二醇修饰聚多巴胺包被多西他赛纳米结晶
取实施例1所得聚多巴胺包被多西他赛纳米结晶混悬液4mL，加入5mg PEG，室温下电磁搅拌12小时，8000rpm离心15分钟，弃去上清，以纯水分散沉淀物，即为聚乙二醇修饰聚多巴胺包被多西他赛纳米结晶，平均粒径约218.3nm，4度冰箱储存40天后分散性良好，粒径无明显增长。
Claims (4)
1.一种制备药物纳米结晶制剂的方法，其特征在于：所述方法通过将难溶性药物多西他赛、多巴胺溶液和研磨珠置于研磨杯中，以球磨仪进行介质研磨制得，其中多巴胺溶液含有浓度为0.01～1％(w/v)的多巴胺和总浓度在1～200mM范围内的碳酸氢钠、枸橼酸钠-枸橼酸缓冲对或磷酸盐缓冲对,药物和聚多巴胺比例范围在20:1～1:1(w/w)。
2.根据权利要求1所述方法所制得的药物纳米结晶制剂。
3.根据权利要求2所述的制剂，其特征在于：所述制剂为混悬液或冻干品。
4.权根据利要求3所述的制剂，其特征在于：所述制剂用于局部注射给药，口服给药，阴道、鼻腔、口腔、直肠、眼部粘膜途径给药，膀胱内灌注给药或手术切缘用药。
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