CN108379593A - 一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法 - Google Patents
一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法 Download PDFInfo
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- CN108379593A CN108379593A CN201810519391.6A CN201810519391A CN108379593A CN 108379593 A CN108379593 A CN 108379593A CN 201810519391 A CN201810519391 A CN 201810519391A CN 108379593 A CN108379593 A CN 108379593A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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Abstract
本发明公开了一种制备氟苯尼考‑壳聚糖/长链羧酸纳米胶束冻干粉的方法,具体包括如下步骤:(1)先溶解得到壳聚糖衍生物的溶液I;(2)将长链羧酸溶解,制得溶液Ⅱ;(3)将溶液I和溶液Ⅱ混合后,加入催化剂,控制体系酸碱度,在超声条件下反应得到壳聚糖‑长链羧酸自组装纳米胶束和催化剂的混合液;(4)混合液经离心分离、透析处理、冷冻干燥洗涤,得到壳聚糖‑长链羧酸纳米胶束;(5)壳聚糖‑长链羧酸纳米胶束在超声条件下与氟苯尼考混合,经过滤、干燥得到本发明的固体产品。具有操作方便、稳定、原料来源丰富等优点。采用了自组装和超声波粉碎的方法,结果使胶束更加致密、性能更加稳定,具有很好经济开发潜力。
Description
技术领域
本发明属于新药研发技术领域,具体涉及一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法。
背景技术
氟苯尼考(Florfenicol,Flo)是新一代氯霉素类动物专用广谱抗生素,对多种革兰氏阳性菌、革兰氏阴性菌及支原体等具有较强的抗菌活性,对溶血性巴氏杆菌、多杀性巴氏杆菌、猪胸膜肺炎放线杆菌高度敏感,且氟苯尼考能通过血脑屏障对动物细菌性脑膜炎有很好的治疗效果。体外试验表明,氟苯尼考抗菌活性明显优于氯霉素、四环素、氨苄青霉素,在动物疾病防治上有广阔的应用前景。但氟苯尼考几乎不溶于水,只溶于部分有机溶剂,其普通制剂生物利用度较低,使用成本较高等缺陷限制了其广泛应用。
研究表明,对于难溶性或亲脂性药物,可采用成盐、超细粉碎化及形成络合物等改变药物的物理化学性质的方法提高药物的溶解度和溶出速率,但这些方法都有一定的局限性,如中性化合物不适合制成盐类,超细粉碎得到的药物极细粉会降低药物的稳定性,有些药物难以形成络合物等。随着纳米技术的发展及其在医药领域的应用,纳米生物技术在增加难溶药物的溶解度、靶向定位给药、药物缓控释、疾病的诊断和辅助治疗等方面有了很大发展。在增加难溶药物溶解度方面,目前常用的纳米材料有纳米胶束,纳米粒,固体纳米脂质体等,其中纳米胶束是由具有两亲性聚合物在分子间作用力的作用下相互聚集形成的一种具有核/壳结构和纳米特性的材料,与普通胶束相比,纳米胶束具有更低的临界胶束浓度和更小的粒径,能在生理环境中表现出更好的生理活性。研究表明,在药物载体方面,纳米胶束的应用前景广阔,如将其应用于难溶性药物新制剂开发,不仅能够提高难溶性药物的溶解度、生物利用度,而且还可以降低其毒副作用。
壳聚糖是天然大分子甲壳素通过脱乙酰基等而得的水溶性衍生物,它不仅具有良好的生物可降解性,生物粘附性和生物相容性,而且还具有消炎,抗菌等大多数聚合物所不具备的功能,壳聚糖分子富含高活性的游离的羟基和氨基,如在壳聚糖分子链上引入亲水基团及疏水基团可获得一类结构新颖的两亲性壳聚糖衍生物,因此,壳聚糖在药物研究领域的应用为世人所瞩目。
发明内容
针对现有技术中氟苯尼考的普通制剂存在的生物利用度较低,使用成本较高等缺陷限制了其广泛应用的问题,本发明的目的在于提供一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,即以壳聚糖衍生物为主要载体辅料制备可溶性的氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,以弥补已有技术的不足。
本发明采取的技术方案为:
一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,具体包括如下步骤:
(1)采用壳聚糖衍生物为原料,先溶解得到质量浓度为4%-12%的壳聚糖衍生物的溶液I;
(2)将长链羧酸溶解,制得质量浓度为1%-10%的溶液Ⅱ;
(3)将步骤(1)中的溶液I和步骤(2)中的溶液Ⅱ按质量比为0.1-6混合,然后进行探头超声处理并向其中加入催化剂,加入pH调节试剂控制体系酸碱度为pH为1-12,在超声条件下,通过控制反应温度5-70℃、反应时间1-2h,即得到壳聚糖-长链羧酸自组装纳米胶束和催化剂的混合液;
(4)壳聚糖-长链羧酸自组装纳米胶束和催化剂的混合液经离心分离、透析处理、冷冻干燥洗涤,得到壳聚糖-长链羧酸纳米胶束;
(5)壳聚糖-长链羧酸纳米胶束,在超声条件下将其加入到有机分散相中与氟苯尼考混合,透析处理,最后经过滤、干燥得到本发明的固体产品。
进一步的,所述步骤(1)中的壳聚糖衍生物的脱乙酰度范围是50%-98%,分子量为10,000Da-2,000Da。
进一步的,所述步骤(1)中的壳聚糖衍生物包括部分脱乙酰基几丁质、全部脱乙酰基几丁质(即氨基多糖)、羧甲基氨基多糖、羟乙基氨基多糖、羟丙基氨基多糖、氨基多糖季氨盐或聚乙烯醇接枝氨基多糖。
进一步的,所述步骤(2)中的长链羧酸为棕榈酸、油酸、共轭亚油酸、顺-15-二十四碳烯酸、脂蜡酸或亚油酸。
进一步的,所述步骤(3)中的催化剂为EDC、NHS、DCC、DIC、HOBt、PyBop、DIEA中的任意两种的组合。
更进一步的,所述步骤(3)中的催化剂采用EDC和NHs催化剂联合应用,EDC、NHS按照质量比(1-3):(2-6)混合。
本反应体系的催化剂,也可称活化剂,如EDC在一定的pH值下可以活化长链羧酸的羧基,使其能够与氨基多糖的氨基发生缩合反应,NHS的存在可以使这种缩合反应的效率大大提高。
进一步的,所述步骤(3)和步骤(5)中的超声条件一致且均为:控制超声输出功率10-200w,超声时间2-12s,间隔时间4-16s,超声次数60-150次。
进一步的,所述步骤(3)中pH调节试剂为碳酸氢铵、氢氧化钠、氨水、氢氧化钾、盐酸或醋酸中的任意一种。
进一步的,所述步骤(4)和步骤(5)中透析处理所使用的透析袋截留分子量(MwCO)为6kD-8kD或12kD-14kD或8kD-10kD;步骤(4)中冷冻干燥温度为-20℃--40℃,时间为24-48h。
进一步的,所述步骤(5)中分散相为乙醇、低浓度醋酸、甲醇、异丙醇或正丁醇中的任意一种。氟苯尼考水溶性很差,所以,是先将氟苯尼考溶解在有机分散相中,有利于提高溶解性,再与壳聚糖-长链羧酸纳米胶束混合,最终制备氟苯尼考壳聚糖-长链羧酸纳米胶束冻干粉。
进一步的,所述步骤(5)中壳聚糖-长链羧酸纳米胶束与氟苯尼考按照质量比(1-6):(1-4)混合,得到的氟苯尼考-壳聚糖/长链羧酸纳米胶束通过20-45℃干燥便得到胶束制品,便于储存和运输,还可以提高制剂的稳定性。
本发明的有益效果为:
本发明利用壳聚糖糖链上存在的-NH2等高活性位点,在催化剂的作用下首先与长链羧酸的羧基进行化学嫁接形成含有亲水性壳聚糖部分和疏水性长链羧酸部分的具有两亲性的阳离子接枝聚合物,随后该聚合物在水性介质中在一定条件下形成内部疏水、外部亲水的阳离子聚合物胶团,再经超声分散、过滤透析、冷冻干燥最终制得目标产物-水溶性的氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉,经查新证明国内外无类同报告,该研究对于提高氟苯尼考的疗效,降低其不良反应,并为开发新型氟苯尼考替代药物以及适合畜禽群体给药的氟苯尼考饮水剂提供了新的制造技术,具有巨大的社会效益及经济效益。
本发明具有操作方便,制备技术工艺简便稳定和制造成本低廉等优点。本发明对原材料有广泛的适用性,所有具有游离氨基的甲克质衍生物均可以适用。因此,本发明的原料来源十分广泛。本发明的重要意义还在于纳米胶束制备中采用了自组装和超声波粉碎的方法,结果使胶束更加致密、性能更加稳定。本发明采用的材料安全无毒副作用、具有良好的生物相容性、生物可降解性、成束性能好等特点。本发明开发得到一种新型氟苯尼考替代药物,具有良好的研究和开发应用前景。因此,该发明技术具有很好经济开发潜力。
附图说明
图1为本发明实施例2中的氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉样品图。
图2为本发明实施例2中的壳聚糖(CS)、长链羧酸(LCCA)和壳聚糖-长链羧酸阳离子接枝聚合物(CS-LCCAcomplex)的红外谱图。
图3为本发明实施例2中的CS-LCCA阳离子接枝聚合物(CS-LCCAcomplex)、CS-LCCA空白纳米胶束(CS-LCCAnanomicelle)、Flo、Flo-CS-LCCA载药纳米胶束的红外谱图。
图4(a)为本发明实施例2中的CS-LCCA接枝聚合物(CS-LCCAcomplex)纳米胶束的SEM图片。
图4(b)为本发明实施例2中的CS-LCCA空白纳米胶束(CS-LCCAnanomicelle)的SEM图片。
图4(c)为本发明实施例2中的Flo-CS-LCCA载药纳米胶束的SEM图片。
图5(a)为本发明实施例2中的CS-LCCA接枝聚合物(CS-LCCAcomplex)的TEM图。
图5(b)为本发明实施例2中的CS-LCCA空白纳米胶束(CS-LCCAnanomicelle)的TEM图。
图5(c)为本发明实施例2中的Flo-CS-LCCA纳米胶束的TEM图。
具体实施方式
下面结合附图进一步说明本发明。
实施例1
先将聚乙烯醇接枝氨基多糖加入去离子水中完全溶解,制得溶液I,再将棕榈酸加入乙醇中溶解,制得溶液Ⅱ,将溶液I和溶液Ⅱ混合,然后进行探头超声处理并向其中加入DCC、HOBt催化剂,DCC和HOBT按照质量比(1-3):(2-6)混合,该实施例中选择DCC和HOBT按照质量比1:2混合,加入pH调节试剂控制体系酸碱度pH 1,控制超声输出功率10w,超声时间12s,间隔时间4s,超声次数150次;通过控制反应温度5℃、反应时间2h,即得到聚乙烯醇接枝氨基多糖-棕榈酸自组装纳米胶束和催化剂的混合液,经分离、透析、冷冻干燥洗涤,得到聚乙烯醇接枝氨基多糖-十六烷酸纳米胶束。在超声条件下将其加入到乙醇中与氟苯尼考(FF)混合,控制超声输出功率10w,超声时间12s,间隔时间4s,超声次数150次;置于透析袋内透析处理,最后经过滤、干燥得到总收率为20.4%、白色粉末状本发明的固体产品。
实施例2
先将氨基多糖加入去离子水中完全溶解,制得溶液I,再将共轭亚油酸加入低浓度醋酸中溶解,制得溶液Ⅱ,将溶液I和溶液Ⅱ混合,然后进行探头超声处理并向其中加入EDC、NHS催化剂,EDC和NHS按照质量比(1-3):(2-6)混合,该实施例中选择EDC和NHS按照质量比2:5混合,加入pH调节试剂控制体系酸碱度pH 6,控制超声输出功率100w,超声时间10s,间隔时间10s,超声次数100次;通过控制反应温度35℃、反应时间1.5h,即得到氨基多糖-共轭亚油酸自组装纳米胶束和催化剂的混合液,经分离、透析、冷冻干燥洗涤,得到氨基多糖-共轭亚油酸纳米胶束。在超声条件下将其加入到低浓度醋酸中与氟苯尼考(FF)混合,控制超声输出功率100w,超声时间10s,间隔时间10s,超声次数100次;置于透析袋内透析处理,最后经过滤、干燥得到总收率为25.36%、细粉状浅黄色本发明的固体产品。
催化剂的选择和配比对CS-LCCA接枝聚合物收率具有较大的影响,具体如下表1所示:
表1催化剂种类对CS-LCCA接枝聚合物收率的影响
表1所示,采用EDC和NHS复配的催化剂催化壳聚糖糖链上的-NH2与长链羧酸的羧基进行化学嫁接,CS-LCCA接枝聚合物收率显著提高。
实施例3
先将氨基多糖季氨盐加入去离子水中完全溶解,制得溶液I,再将顺-15-二十四碳烯酸加入异丙醇中溶解,制得溶液Ⅱ,将溶液I和溶液Ⅱ混合,然后进行探头超声处理并向其中加入PyBop、DIEA催化剂,PyBop和DIEA按照质量比(1-3):(2-6)混合,该实施例中选择PyBop和DIEA按照质量比1:3混合,加入pH调节试剂控制体系酸碱度pH 12,控制超声输出功率50w,超声时间8s,间隔时间10s,超声次数100次;通过控制反应温度50℃、反应时间1.8h,即得到氨基多糖-顺-15-二十四碳烯酸自组装纳米胶束和催化剂的混合液,经分离、透析、冷冻干燥洗涤,得到氨基多糖-顺-15-二十四碳烯酸纳应为米胶束。在超声条件下将其加入到异丙醇中与氟苯尼考(FF)混合,控制超声输出功率50w,超声时间8s,间隔时间10s,超声次数100次;置于透析袋内透析处理,最后经过滤、干燥得到总收率为21.13%、白色粉末状本发明的固体产品。
实施例4
先将羧甲基氨基多糖加入去离子水中完全溶解,制得溶液I,再将油酸加入甲醇中溶解,制得溶液Ⅱ,将溶液I和溶液Ⅱ混合,然后进行探头超声处理并向其中加入EDC、DIC催化剂,EDC和DIC按照质量比(1-3):(2-6)混合,该实施例中选择EDC和DIC按照质量比3:2混合,加入pH调节试剂控制体系酸碱度pH7,控制超声输出功率120w,超声时间6s,间隔时间10s,超声次数120次;通过控制反应温度20℃、反应时间2h,即得到羧甲基氨基多糖-油酸自组装纳米胶束和催化剂的混合液,经分离、透析、冷冻干燥洗涤,得到羧甲基氨基多糖-油酸纳米胶束。在超声条件下将其加入到甲醇中与氟苯尼考(FF)混合,控制超声输出功率120w,超声时间6s,间隔时间10s,超声次数120次;置于透析袋内透析处理,最后经过滤、干燥得到总收率为23.9%,浅褐色粉末状本发明的固体产品。
实施例5
先将羟乙基氨基多糖加入去离子水中完全溶解,制得溶液I,再将脂蜡酸加入正丁醇中溶解,制得溶液Ⅱ,将溶液I和溶液Ⅱ混合,然后进行探头超声处理并向其中加入NHS、DIC催化剂,NHS和DIC按照质量比(1-3):(2-6)混合,该实施例中选择NHS和DIC按照质量比1:6混合,加入pH调节试剂控制体系酸碱度pH6,控制超声输出功率200w,超声时间2s,间隔时间4s,超声次数60次;通过控制反应温度60℃、反应时间1.2h,即得到羟乙基氨基多糖-脂蜡酸自组装纳米胶束和催化剂的混合液,经分离、透析、冷冻干燥洗涤,得到羟乙基氨基多糖-脂蜡酸纳米胶束。在超声条件下将其加入到正丁醇中与氟苯尼考(FF)混合,控制超声输出功率200w,超声时间2s,间隔时间4s,超声次数60次;置于透析袋内透析处理,最后经过滤、干燥得到总收率为26.4%、白色微黄粉末状本发明的固体产品。
产品检测:本申请的上述实施例2中制备得到的固体产品的相关实验数据如说明书附图所示,具体如下:
如图1所示氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉样品图。
如图2所示,壳聚糖的红外图谱特征峰包括407.58cm-1(N-H和O-H伸缩振动)、2932.89cm-1(C-H伸缩振动)、1558.22cm-1(N-H弯曲变形振动)吸收峰。壳聚糖-长链羧酸接枝聚合物红外图谱中位于1558.22cm-1的壳聚糖特征峰消失,而在1575.91cm-1和1542.82cm-1处形成新的吸收峰,这是由于复合物形成-NH3 +所致,而吸收峰2917.47cm-1、2849.77cm-1、724.29cm-1的出现说明阳离子接枝聚合物中含有长链羧酸长链。1648.53cm-1处的吸收峰是离子化羧基的特征峰,而吸收峰1419.52cm-1是酰胺中C-N伸缩振动形成的特征峰,说明长链羧酸的羧基和壳聚糖的氨基之间形成了一个酰胺键,即壳聚糖和长链羧酸不是简单地物理吸附,而是通过壳聚糖上游离的氨基和长链羧酸上游离的羧基形成酰胺键的形式结合。
如图3所示,CS-LCCA空白纳米胶束的红外图谱与CS-LCCA阳离子接枝聚合物的红外图谱比,吸收峰的位置和强度无明显变变化,说明在胶束形成过程中没有形成新的化学键,即CS-LCCA阳离子接枝聚合物在形成胶束的过程不是化学反应过程,而是物理过程,Flo-CS-LCCA载药纳米胶束的红外图谱与CS-LCCA空白纳米胶束的红外图谱比,吸收峰亦无明显变化,说明药物CS-LCCA空白纳米胶束装载疏水性药物Flo的过程也是物理过程。
如图4所示,CS-LCCA接枝聚合物呈类球形,表面有褶皱,CS-SA空白纳米胶束和Flo-CS-LCCA载药纳米胶束呈球形、表面形貌较为规则、无褶皱。
如图5所示,CS-LCCA接枝聚合物经超声处理后,形成球形的、内部具有空腔结构的CS-SA空白纳米胶束,而载入药物后形成的Flo-CS-LCCA载药纳米胶束内部空腔结构消失,此可能与Flo与胶束内核通过疏水性相互作用、静电作用和氢键作用进入了胶束内部,从而使Flo的溶解度和生物利用度提高有关。
以上所述并非是对本发明的限制,应当指出:对于本技术领域的普通技术人员来说,在不脱离本发明实质范围的前提下,还可以做出若干变化、改型、添加或替换,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,具体包括如下步骤:
(1)采用壳聚糖衍生物为原料,先溶解得到质量浓度为4%-12%的壳聚糖衍生物的溶液I;
(2)将长链羧酸溶解,制得质量浓度为1%-10%的溶液Ⅱ;
(3)将步骤(1)中的溶液I和步骤(2)中的溶液Ⅱ按质量比为0.1-6混合,然后进行探头超声处理并向其中加入催化剂,加入pH调节试剂控制体系酸碱度为pH为1-12,在超声条件下,通过控制反应温度5-70℃、反应时间1-2h,即得到壳聚糖-长链羧酸自组装纳米胶束和催化剂的混合液;
(4)壳聚糖-长链羧酸自组装纳米胶束和催化剂的混合液经离心分离、透析处理、冷冻干燥洗涤,得到壳聚糖-长链羧酸纳米胶束;
(5)壳聚糖-长链羧酸纳米胶束,在超声条件下将其加入到有机分散相中与氟苯尼考混合,透析处理,最后经过滤、干燥得到本发明的固体产品。
2.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(1)中的壳聚糖衍生物的脱乙酰度范围是50%-98%,分子量为10,000Da-2,000Da。
3.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(1)中的壳聚糖衍生物包括部分脱乙酰基几丁质、全部脱乙酰基几丁质(即氨基多糖)、羧甲基氨基多糖、羟乙基氨基多糖、羟丙基氨基多糖、氨基多糖季氨盐或聚乙烯醇接枝氨基多糖。
4.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(2)中的长链羧酸为棕榈酸、油酸、共轭亚油酸、顺-15-二十四碳烯酸、脂蜡酸或亚油酸。
5.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(3)中的催化剂为EDC、NHS、DCC、DIC、HOBt、PyBop、DIEA中的任意两种的组合。
6.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(3)和步骤(5)中的超声条件一致且均为:控制超声输出功率10-200w,超声时间2-12s,间隔时间4-16s,超声次数60-150次。
7.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(3)中pH调节试剂为碳酸氢铵、氢氧化钠、氨水、氢氧化钾、盐酸或醋酸中的任意一种。
8.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(4)和步骤(5)中透析处理所使用的透析袋截留分子量(MwCO)为6kD-8kD或12kD-14kD或8kD-10kD;步骤(4)中冷冻干燥温度为-20℃--40℃,时间为24-48h。
9.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(5)中分散相为乙醇、低浓度醋酸、甲醇、异丙醇或正丁醇中的任意一种。
10.根据权利要求1所述一种制备氟苯尼考-壳聚糖/长链羧酸纳米胶束冻干粉的方法,其特征在于,所述步骤(5)中壳聚糖-长链羧酸纳米胶束与氟苯尼考按照质量比(1-6):(1-4)混合,得到的氟苯尼考-壳聚糖/长链羧酸纳米胶束通过20-45℃干燥便得到胶束制品。
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CN110064058A (zh) * | 2019-05-09 | 2019-07-30 | 青岛科技大学 | 一种阿司匹林/壳聚糖修饰碳纳米管给药体系的制备方法 |
CN113045687A (zh) * | 2021-03-18 | 2021-06-29 | 山东大学 | 一种聚合物、纳米自组装体、药物递送系统及其制备方法和应用 |
CN113045687B (zh) * | 2021-03-18 | 2022-04-19 | 山东大学 | 一种聚合物、纳米自组装体、药物递送系统及其制备方法和应用 |
CN114652637A (zh) * | 2022-04-06 | 2022-06-24 | 南京工业大学 | 基于阳离子羟基磷灰石的纳米制剂、制备、应用、药物组合物、喷雾剂、漱口水及水凝胶 |
CN114652637B (zh) * | 2022-04-06 | 2023-06-20 | 南京工业大学 | 基于阳离子羟基磷灰石的纳米制剂、制备、应用、药物组合物、喷雾剂、漱口水及水凝胶 |
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