CN108136034A - 药物缓释载体及制备方法 - Google Patents
药物缓释载体及制备方法 Download PDFInfo
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- CN108136034A CN108136034A CN201680041320.9A CN201680041320A CN108136034A CN 108136034 A CN108136034 A CN 108136034A CN 201680041320 A CN201680041320 A CN 201680041320A CN 108136034 A CN108136034 A CN 108136034A
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Abstract
可具有药物缓释作用的DDS载体的制造方法。特征为,将缓释药物保持在PEG‑羧基高分子聚合物中。所选择的高分子以含羧基的多糖类最适合使用。含有PEG‑羧基的高分子聚合物是通过将聚乙二醇连接到含羧基的高分子上而获得的化合物。使用含羧基的多糖类作为原料时,可以在三嗪缩合剂的存在下,利用胺化的PEG与含羧基的多糖类化合物发生缩合反应来制备。此外,也可通过利用PEG与含羧基的多糖类化合物在酸性条件下的缩合反应来制备PEG‑羧基多糖聚合物。
Description
【技术领域】
开发一种使用新型药物传递系统的药物缓释载体。
【背景技术】
特定盐溶液与高分子水溶液混合、或是不同高分子溶液混合,在满足浓度、温度等一定条件时会出现液-液两相分离。分离的两个液相系统称为双水相系统(Aqueous TwoPhase System)。向双水相系统中加入蛋白质等基质,由于基质在两相中的扩撒不同会出现不均等分配。已发现可构成双水相系统的多种亲水性高分子或盐的组合,并应用到蛋白类药物的提取工艺中。
对由亲水性高分子溶液组成的双水相系统的物理化学研究发现,高分子的分子单体间的相互作用力是相分离的原因。不同高分子共存环境对比单一分子存在环境,由于锁状链接使溶液混合熵变得非常小,与之相对的分子单体间排斥作用增大,造成两相分离。双水相系统是分离·精制的常用手段。
双水相萃取法的优点有以下4点:
(1)不使用固相,则可避免由吸附造成的活性物质的结构破坏·变性,同时亲水性高分子共存使系统稳定可以在常温下分离。
(2)由于两相间界面张力有细微差别,使得两相混合后产生稳定的微细液滴悬浮其中,易于迅速达成分配平衡。
(3)向分离目标物质中导入亲水基团会使分离的特异性增大。
(4)由于分配系统与系统总体积、两相体积比、分离对象浓度影响不大,可以很容易地以实验室小规模的实验结果为基础进行扩大。
另一方面,药学与医学等领域包括蛋白类药物在内,低分子药物的缓释逐渐被重视而目前也没有十分妥善的对策。因此,人们对承担缓释作用的载体在如注射剂、内服剂、体内嵌入式制剂、微针制剂、经皮给药制剂等多种剂型中的使用寄予了极高的期望
已有许多报告介绍了利用双水相系统制备缓释性的药物传递系统(drugdelivery system,下称DDS)。例如,以聚乙二醇水溶液为连续相,以可交联葡萄糖聚合物为分散相的缓释给药(专利文献1);以水溶性多糖溶液为连续相,以聚乙二醇二丙烯酸酯水溶液为分散相制备的乳胶,被用作蛋白质(细胞因子)的缓释给药(专利文献2)等报导。以下,将聚乙二醇以PEG缩写表示。
然而,蛋白类药物在体内缓释给药时,利用聚乙二醇水溶液与可交联葡萄糖聚合物水溶液的相分离,由于分散相的大小、两相分配平衡等难以控制,导致药物的缓释难以稳定。
【现有技术文献】
【专利文献】
【专利文献1】特表2001-504828号公报
【专利文献2】特表2006-517523号公报
【发明内容】
【本发明要解决问题】
本发明的目的是提供以双水相系统为原理开发的新DDS载体。
虽然目前正以应用于蛋白类药物缓释制剂为目的,对双水相分配现象进行研究,但是PEG连接的高分子用作DDS载体的可用性并未明确。并且,PEG连接的高分子的制作法亦未确立,PEG相中蛋白质的分配条件控制、受控释放等问题也从未被讨论过。本发明针对高分子中,拥有PEG重复单元结构的一端氨化PEG(PEG-NH2)嫁接化合物,提供新制备方法。并且,以将这种化合物用于蛋白类药物的缓释性DDS载体为研究目的。
【解决问题的方法】
本发明为解决上述课题,开发连有PEG的高分子聚合物的DDS载体,此外,连有PEG的多糖聚合物也为本发明特征。
此处,PEG-羧基高分子(多糖)聚合物是指,PEG连接于含有羧基的高分子(多糖)主链上的化合物。向PEG导入氨基,高分子(多糖)导入羧基,或使用本来含有羧基的高分子(多糖),在无水环境中利用碱基或者酸性催化剂进行酯化反应,形成高分子(多糖)羧基与PEG末端羟基缩合的化合物。含有PEG的高分子聚合物的构造,可由1H-NMR光谱确认。
PEG与含羧基高分子溶解于水中形成双水相系统。向其中添加蛋白类药物,溶解后蛋白类药物极易富集于PEG相中。但是,利用蛋白类药物浓缩于PEG相的双水相系统向身体给药时,PEG扩散于体液中(血液、细胞间液)使蛋白类药物也立刻扩散,不可能达到缓释效果。
将PEG连接在富含羧基的高分子上,使整体分子量显著上升,不再溶解于水中或者体液中,而是成为膨胀体,抑制其在体液中的扩散。利用这种方式,蛋白类药物的缓释成为了可能。这也是本发明的特征,利用蛋白类药物易浓缩于双水相系统中的PEG相的原理,将PEG连接在含羧基高分子上,防止PEG在体液中扩散从而使得DDS制剂可被实际应用。PEG-羧基高分子聚合体的高分子最好使用水溶性,尤其是水溶性高分子中的聚丙烯酸及其聚合物、或者可以优选多糖类物质。含羧基多糖类中,优选分子内含羧基的黄原胶、结冷胶、海藻酸、羧甲基纤维素、透明质酸等物质。
含羧基水溶性高分子分子量以5×104~5×106道尔顿范围为佳。分子量在此范围内,不同的含羧基水溶性高分子也可混合,同样的含羧基水溶性高分子也可混合。另外,分子量在此范围内,与分子量小于范围的不同高分子也可混合。
含羧基多糖类中,透明质酸(以下略称为“HA”)最适宜使用。此时所用透明质酸为含钠盐或者含钾盐的金属盐形态也可,以下,连接有PEG的含羧基透明质酸聚合物将被略写为“PEG-graft-HA”。
已知有多种方法,使含羧基多糖类化合物与PEG进行缩合化学反应。这些方法都能被本发明使用,而使用氨化PEG的缩合反应进行得最顺利。PEG与透明质酸的羧基聚合中,PEG的氨基与透明质酸的羧基在以水为主的溶液环境中,经过缩合剂的催化进行缩合反应。同时,在非水环境中,将透明质酸与PEG进行酯化反应形成聚合物更是一种十分有效的方法。这种反应在酸性环境中进行,PEG与含羧基多糖类进行缩合,能制造出PEG-羧基多糖类聚合物。该反应特征是,含有羧基的多糖类(尤其是透明质酸)与PEG的结合是酯键的结合。在非水环境中将透明质酸酯化时,使用硫酸、高氯酸等酸进行酯化反应。非水溶剂可以是四氢呋喃(THF)、氯仿、N,N-二甲基乙酰胺(DMA)等,也可以不使用溶剂在PEG酸性环境下,使透明质酸悬浊其中进行聚合反应。
缩合反应中使用的缩合剂除了可使用二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)等化合物,以下化学式(1)中表示的三嗪类化合物也常被使用。其中,R1、R2指短链(含碳数1-6)烷基,X指卤素原子。当R1、R2为甲基、X为氯时为最常使用的缩合剂4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM)。
【化学式1】
透明质酸是长链多糖类粘多糖的一种。由D-葡萄糖醛酸与N-乙酰基葡糖胺通过β-1,3配糖键相连,组成的双糖单位间则通过β-1,4配糖键相连形成高级多糖。羟基、羧基、相邻两糖结合处的异头碳等大体积的取代基处于立体排斥较小的平伏键上,而所有的氢原子则处于立体排斥大的不安定直立键上。平伏键上置换基形成极性的强亲水性面,而直立键上氢原子为非极性,形成相对疏水性的面。因此,生理溶液中的透明质酸会扩散形成丝带和随机的线圈形状,拥有非常大的体积。
透明质酸的水溶液无色透明、粘度高、呈凝胶状。存在于人身体的关节液与关节软骨中的透明质酸起到减少骨与骨之间摩擦的润滑作用,同时因其具有弹性作用,所有能缓冲应力维护关节的运动。另外,眼球玻璃体中的透明质酸起到支持眼球形状和防止细菌侵入的作用。最后,透明质酸在皮肤中起到保持水分,维持皮肤光洁滋润。
PEG是乙二醇聚合得到的高分子化合物。很早之前就已开始工业制造,在非离子表面活性剂、润滑油、聚氨酯合成中间体、粘合剂、化妆品等制造中用途广泛。更由于其对人体无毒,以“macro goal”的名称被收录入日本医药品添加物记录中。同时,因为肝脏脾脏中的单核吞噬细胞系统产生的巨噬细胞也不捕捉PEG分子,使得其能长时间停留循环于血液中(隐秘性),所以可将蛋白类药物和脂质体等物质连接到PEG上,使这些物质PEG化。本发明对所述PEG的分子量不做特别要求,以分子量在1000以上100万以下为优。同时,对分子量范围内的PEG分子构造不做特别要求。
本发明所述PEG-羧基多糖类聚合体可以用作蛋白类药物和低分子类药物等的DDS载体。尤其适合分子内既有亲水基也有疏水基、以及与PEG亲和性较高的化合物。
本发明对PEG-羧基多糖类聚合体的PEG与羧基多糖类的重量比,虽然不做特别要求,但是PEG:羧基多糖类的重量比在1∶20~1∶0.1为推荐范围。羧基多糖类化合物上缩合的PEG量过少时,聚合物对蛋白类药物和低分子类药物等的亲和性效果较低。同时,羧基多糖类中缩合极大量的PEG会使聚合物制造过程困难。
本发明对PEG-羧基多糖类聚合物的分子量不做特别要求,根据其使用目的选择合适分子量的化合物。医药品所用DDS载体的情况,适合使用分子量200以上20,000万以下的聚合物,也可以混合分子量不同的聚合物使用
本发明适用于以下药物及与之相似的化合物。
蛋白质类药物,例如:胰岛素、艾塞那肽、降钙素、副肾上腺皮质激素、甲状旁腺激素、特立帕肽、胰泌素、催产素、血管紧张素、β-内啡肽、胰高血糖素、抗利尿激素、生长抑素、胃泌素、黄体生成素释放激素、内啡肽、神经降压素、心房利钠肽、生长激素、生长激素释放素、缓激肽、物质P、强啡肽、促甲状腺激素、催乳素、干扰素、白细胞介素、粒细胞集落刺激因子、谷胱甘肽过氧化物酶、超氧化物歧化酶、氨加压素片、生长调节素、内皮素以及这些化合物的盐等。抗原蛋白或病毒片段之类的有流感抗原、破伤风抗原、白喉抗原、乙肝表面抗原、乙肝E抗原等等相似物质。
低分子类药物中,对常规药物以及化妆品原料不做特殊限制,例如:解热镇痛消炎药、类固醇消炎药、血管扩张剂、抗心律不齐药、降血压药、局部麻醉药、荷尔蒙制剂、抗组胺药、全身麻醉药、镇痛催眠药、抗癫痫药、精神药物、骨骼肌松驰剂、自律神经治疗用药、抗帕金森病药、利尿剂、血管收缩剂、呼吸促进剂、麻醉剂等等。
上述解热镇痛消炎药举例为:布洛芬、氟比洛芬、酮基布洛芬等。上述类固醇消炎药举例为:醋酸氢化可的松、曲安奈德、泼尼松龙等等。上述血管扩张剂举例为:盐酸地尔硫卓、硝酸异山梨酯等等。上述抗心律不齐药,例如:盐酸普鲁卡因胺、盐酸美西律等。
上述降血压药举例为:盐酸可乐啶、盐酸小檗胺、卡托普利等。上述局部麻醉药举例为:盐酸丁卡因、盐酸丙胺卡因等。上述荷尔蒙制剂举例为:丙基硫氧嘧啶、雌二醇、雌三醇、黄体激素等。上述抗组胺药举例为:盐酸苯海拉明、扑尔敏马来酸盐等。
上述全身麻醉药举例为戊巴比妥钠等。上述镇痛催眠药举例为:异戊巴比妥、苯巴比妥等。上述抗癫痫药举例为苯妥英钠等。上述精神药物举例为:盐酸氯丙嗪、盐酸丙咪嗪、利眠宁、地西泮等。上述骨骼肌松驰剂举例为:盐酸苏泊松、盐酸乙哌立松等。
上述自律神经治疗用药举例为:溴化新斯的明、氯化二乙酰胆碱等。上述抗帕金森病药举例为盐酸金刚烷胺等。上述利尿剂举例为:氢氟噻嗪、硝酸异山梨、呋塞米等。上述血管收缩剂举例为盐酸苯肾上腺素等。上述呼吸促进剂举例为:盐酸洛贝丁、双吗啉胺、盐酸纳洛酮等。上述麻醉剂举例为:吗啡盐酸盐、盐酸可卡因、盐酸吡啶等。
上述化妆品原料举例为:抗坏血酸棕榈酸酯、曲酸、4-正丁基间苯二酚、氨甲环酸、脂溶性甘草提取物、维生素A衍生物等美白成分;视黄醇、视黄酸、醋酸视黄醇酯、视黄醇棕榈酸酯等抗皱成分;生育酚乙酸酯、辣椒素、苯甲酸香草酰胺等促血液循环成分;复盆子酮、月见草提取物、海藻提取物等减肥成分;异丙基甲基苯酚、光敏剂、氧化锌等抗菌成分;维生素D2、维生素D3、维生素K等维生素类。
PEG-graft-HA作为药物缓释的载体,适用于多种剂型。例如,注射剂、口服制剂、体内植入型制剂、经皮给药剂型、微针制剂;在化妆水、化妆乳液、美容霜等化妆品的用途上也让人期待。
上述注射剂可以是药品的溶液、悬浊液、乳浊液、以及临用前配置成溶剂或混悬液的药物制剂,皮下给药、通过皮肤或粘液直接向体内给药的制剂。注射剂的种类可以是溶液,以及配合药物自身物化性质制备的水溶性注射液、非水溶性注射液、混悬注射液、乳浊注射液、溶解或者混悬后使用的固体注射剂。
上述口服制剂的种类可以是颗粒、细颗粒、粉末、糖衣片、片剂、散剂、(微)胶囊、咀嚼片、糖浆、果汁、溶液、悬浊液、乳浊液等。
上述体内植入型制剂是植入皮下的固体制剂,包括前述固体注射剂和其他固体制剂。前述(微)胶囊与其后所述微针制剂也可以作为植入型制剂使用。
上述经皮给药制剂是通过局部涂抹或黏附,使药物穿透皮肤或粘膜达到给药作用的制剂。制剂包括含有有效药物成分的液体物质、软膏剂、霜剂、胶布制剂、膏药制剂、巴布剂等。
上述微针制剂是1或者复数的微细针状制剂,也包括在底板表面附着复数微针的整体剂型。微针自身的形状可以是水溶性或者水溶胀性树脂形成的圆锥形、截头圆锥形、火山形等形状。而举例1根微针的大小,可以是针底宽度或者直径为0.15~1.0mm、高度为0.1~2.0mm程度。前述水溶性或者水溶胀性树脂可指在体内溶解或者会膨胀树脂,例如糖原、糊精、葡聚糖、硫酸葡聚糖、硫酸软骨素钠、羟丙基纤维素、壳聚糖、海藻酸、琼脂糖、几丁质、壳聚糖、聚麦芽三糖、淀粉精、淀粉、透明质酸等多糖类、胶原、明胶、白蛋白等蛋白质、聚乙烯醇、羧乙烯聚合物、聚丙烯酸钠、聚乙烯吡咯烷酮、聚乙二醇等合成高分子,其中以透明质酸、胶原蛋白、明胶、聚乙烯吡咯烷酮及聚乙二醇最适宜使用。以此,PEG-graft-HA作为微针材料既可以单独使用,也可以与上述水溶性或水溶胀性树脂中挑出一种或多种高分子并用。
上述化妆水、化妆乳液又或是美容霜均可作为化妆用品使用,亦可用于准药品与药妆分类的产品。
PEG-graft-HA作为药物缓释的载体,适用于多种剂型。例如,注射剂、口服制剂、体内植入型制剂、经皮给药剂型、微针制剂;在化妆水、化妆乳液、美容霜等化妆品的用途上也让人期待。
注射剂、口服制剂、体内植入型制剂、经皮给药剂型、微针制剂等药品制剂是以PEG-羧基多糖类聚合体为载体,与有效成分按常规制剂化方法制备而得。此外,根据制剂需求可以添加各种法律允许的药品添加物质。药用辅料可根据制剂剂型选择适宜物质,例如:赋形剂、稀释剂、添加剂、崩解剂、粘合剂、包衣剂、润滑剂、助流剂、润滑剂、助流剂、香料、甜味剂、增溶剂、溶剂、基质、胶粘剂等。
PEG-羧基多糖类聚合体作为载体使用于化妆水、化妆乳液或是美容霜中,可与化妆品原料、任意的有效成分等混合用常规方法制备制剂。PEG-羧基多糖类聚合体中,PEG-graft-HA所含透明质酸自身具有保湿与抗皱等效果,缓释化后的持续效果值得期待。
【发明效果】
向PEG与含羧基多糖类溶解于水形成的双水相系统中添加蛋白质类药品并使其溶解,蛋白质类药品会在PEG相中富集。只是由于PE6会在体液(血液、细胞间液)中扩散,为利用双水相系统达到药物缓释效果带来困难。而将PEG连接在多糖类化合物羧基上的PEG-羧基多糖类聚合体由于分子量变大,在体液中的扩散可被抑制,从而起到缓释效果。这种效果不仅仅局限于透明质酸(HA)连接PEG的聚合物,在其他含羧基的多糖类上也被发现。下面以HA为代表,举例说明。
PEG-graft-HA具有以下性质。
1.对蛋白质、低分子类等药物具有良好的吸附性,因此是这些药物的有效的缓释载体。
2.由于与PEG聚合,HA的生物体内降解过程变缓,使聚合体作为药物载体的持续存在时间延长。
根据本发明中所述PEG-graft-HA的制造方法,使用通式(1)所示化合物作为缩合剂,在主要以水作为溶剂的环境中反应,快速得到高产率PEG-graft-HA化合物。
【附图说明】
【图1】图1是透明质酸被修饰化合物PEG-graft-HA-1的核磁共振氢谱(1H-NMR)。
【图2】图2是透明质酸被修饰化合物PEG-graft-HA-1的凝胶渗透色谱。
【图3】图3是透明质酸被修饰化合物PEG-graft-HA-1的微针贴片所展示出的抗皱效果。
【图4】图4是透明质酸被修饰化合物抵抗酶分解作用的展示图。横轴为时间(hours)。
【具体实施方式】
以下将详细描述本发明的实例,但是本发明不限于这些实例。
PEG-graft-HA制造时需要将PEG末端氨基化。末端氨基化PEG可以在实验室中制造,更可使用末端氨基化的甲氧基聚乙二醇商品(日本油脂(株)SUNBRIGHT(MEPA-50H)分子量5000)。
PEG-graft-HA的制造过程为,向HA水溶液中搅拌添加末端氨基化的甲氧基聚乙二醇(MEPA-50H)制成混合水溶液,再加入适量的DMTMM进行数小时的缩合反应。反应后,低分子生成物可以通过透析排除。向反应溶液中加入大量丙酮,使反应产物PEG-graft-HA沉淀,可摒除上清液精制产物。之后用冻干、室温干燥等手段得到干燥粉末。
【实施例1】
(PEG-graft-HA-1的制备)
向500ml瓶中加入100ml水,再加入0.1g透明质酸(FCH-SU,分子量8~11万,(株)Kikkoman Biochemifa Company)在室温下搅拌至完全溶解,随后添加末端氨基化的甲氧基聚乙二醇(SUNBRIGHT(MEPA-50H))0.1g(MEPA-50H)同样搅拌至完全溶解。再在室温条件下加入0.1g的DMTMM进行5小时的缩合反应。反应结束后,通过24小时透析除去低分子生成物来精制反应产物。最后,冻干提纯得到PEG-graft-HA-1粉末。
得到的PEG-graft-HA-1溶解于0.01M磷酸缓冲液(pH7.5:以下以“PBS”略称)中制成4WT%水溶液。分光光度计650nm下测得溶液透过率为28%。原料透明质酸与SUNBRIGHT的4WT%水溶液的透過率(650nm)各为95%与100%。这其中的区别可能是由于透明质酸中缩合的PEG引起了微相分离,可凭借此确认PEG-graft-HA的存在。另外,WT%是指重量%,以下同样以此表示。
(透明质酸缩合反应产物的性质)
将实施例1中制备的干燥PEG-graft-HA-1用重水溶解成1WT%的实验溶液。实验装置则使用JEOL-LA300FTNMRSYSTEM(日本电子(株))核磁共振(NMR)设备。数据解析使用JEOLNMR Data Processing Software ALICE2软件。
得到的NMR图如图1所示(1H-NMR(400MHz,D2O):δ(ppm)=1.97的峰来自于透明质酸尾端甲基NHCO-CH3上氢原子;δ(ppm)=3.5-3.7的峰来自于聚乙二醇结构中-CH2CH2O-上氢原子。由该NMR图可以确认透明质酸上聚合的PEG的存在。从两处峰面积上计算出PEG在透明质酸中的缩合率为41%(此处用重量比率来表示缩合率)。
上述缩合率是通过NMR测定,得到的HA尾端甲基上的氢原子与PEG的-CH2CH2O-上氢原子数的比值,再通过计算得到。亦即,缩合率是缩合后的聚合物中PEG与HA的重量比。
观察1H-NMR上的化学位移(相对于内标准物四甲基硅烷TMS),PEG上-CH2CH2O-的氢原子产生的吸收峰在δ(ppm)=3.5-3.7处位置。计算含羧基高分子(多糖类)尾端甲基的固有化学位移峰面积,和PEG上-CH2CH2O-的化学位移峰面积,算出两者比例,求得含羧基高分子(多糖类)上PEG的缩合率。
(PEG-graft-HA-1的凝胶渗透色谱(GPC))
使用带多角度激光光散射检测器的分子排阻色谱(SEC-MALS)来确认缩合反应产物的单一性并测定反应产物的分子量。将实施例1中制备的PEG-graft-HA干燥,溶解于水得到0.1重量%的实验用液。检测条件如下所示:
色谱柱:Shodex PROTEIN GF-710HQ(7.6mmI.D.x 300mm)+Shodex Asahipak GS-510HQ(7.5mmI.D.x 300mm)
注射量:150μL
洗脱液:0.1M Phosphate buffer(pH7.0)
流速:1.0mL/min
检测器:MALS(Multi angle laser light scattering),90度
柱温:26℃
测定所得色谱图如图2所示。色谱峰只有一个单独峰,检测只得到PEG-graft-HA一种物质。未反应的PEG以及透明质酸都未被检测到。计算得到PEG-graft-HA分子量为44.3万。
【实施例2】
(使用PEG-graft-HA-2的胰岛素缓释制剂)
使用FCH-80LE(分子量60~100万、(株)Kikkoman Biochemifa Company)种类的HA代替FCH-SU,其余合成方法均与实施例1相同,得到聚合物PEG-graft-HA-2(49.7mg)与HA-80LF(28.9mg)一起溶解于PBS 0.7ml中,调整HA浓度至4wt%溶液。此时溶液呈白浊状态。
将FITC-Insulin(在胰岛素上标记异硫氰酸荧光素FITC,使测量更简便的自制药剂)0.87mg溶解于上述溶液中,得到黄色透明溶液。将溶液移至透析管(透析膜截留分子量3000购买自SPECTRUMLABO公司)中,浸入装满实验液体(500ml)的500ml烧杯中,并固定透析管使其无法移动。实验液体使用PBS溶液,且该PBS溶液至少提前一日静置于室温中。向烧杯中放置磁力搅拌子,将该烧杯置于磁力搅拌器上,调整转速至145rpm使搅拌子旋转。试验装置上方覆盖保鲜膜,防止实验过程中实验液体的蒸发。每过10小时,迅速从烧杯中心位置取1mL实验液体,取液后立刻补充1mL的PBS溶液,保持总液体量不变。所取实验液体在激发波长495nm和测量波长510~600nm,以及温度25℃条件下检测荧光。通过测量FITC-Insulin在520nm处的荧光强度计算胰岛素释放率。表1为实施例2的实验结果。
用HA代替PEG-graft-HA-2进行相同的FITC-Insulin释放实验。实验结果作为比较例1亦展示在表1中。
【表1】
PEG-graft-HA-2内储存的胰岛素向外部释放的速度,与透明质酸中储存的胰岛素的释放速度比,大幅减缓。由此可知,PEG-graft-HA-2储存的胰岛素缓释效果更好,PEG-graft-HA-2也更适合做DDS缓释载体。
【实施例3】
(PEG-graft-HA-2抗酶降解)
用0.15mole%PBS将实施例2中合成的聚合物PEG-graft-HA-2溶解,制成2WT%的溶液。并且用同样方法制备2WT%的HA溶液。向两种溶液中添加30units/mg HA的透明质酸酶(Hyaluronidase“AMANO”,和光纯药株式会社),检测透明质酸的分子量的降低。
透明质酸酶添加后8小时,测得分子量的降低率(8小时后的分子量/最初分子量):聚合物PEG-graft-HA-2的降低率为70%,而透明质酸的降低率为9%程度。即,8小时的酶反应后,透明质酸分子量降至1/10以下,而PEG-graft-HA-2的分子量仅降低至70%程度。聚合了PEG的透明质酸比未聚合PEG的透明质酸的抵抗酶降解效果更强。
【实施例4】
(在微针上的应用)
用PEG-graft-HA-2制作微针,贴付于本社志愿者额上皱纹部位,检验其抗皱纹的持续效果。为方便肉眼观察,使用医疗用微针(针长800μm)。微针用模板铸造在长半轴1.0cm、短半轴0.6cm的椭圆形微针贴片上,贴付于额上皱纹部位,观察该部位随时间的变化,得到如图3所示结果。
在图三虚线环绕处的深皱纹部位贴付微针,5小时后剥离。图中(a)为使用前;(b)为使用3天后;(c)为使用7天后;(d)显示使用12天后皮肤状态。
一天一次连续使用3天后,隔周再在同一皮肤皱纹部位使用一次,观察皱纹随时间发生的变化。如图3所示,连续使用3天后,皱纹有了明显的变浅效果。之后,随着时间的变化,作用有所降低。但是经过两周时间的观察,发现与使用前相比依旧具有持续抗皱效果。在以往的实验中,普通的透明质酸微针在使用停止7天后皱纹会缓慢回复原样,而PEG-graft-HA由于代谢迟缓,有可能成为持续的抗皱化妆品。
【实施例5】
(通过酯化反应制造透明质酸-PEG聚合物)
实验试剂全部自和光纯药株式会社购入,均为特级试药。
向100g的THF和50g的PEG400中加入透明质酸(FCH-SU,分子量8~11万,(株)Kikkoman Biochemifa Company)6.0g制成悬浊液体,加入浓硫酸1mL在50℃水浴环境下搅拌反应10小时。20小时后将产物取出,进行精制和干燥,得到PEG-HA-5聚合物。
【实施例6】
(通过酯化反应制造透明质酸-PEG聚合物-2)
向70g的PEG400中添加透明质酸(FCH-SU)6.0g制成悬浊液体,加入高氯酸1mL在50℃水浴环境下搅拌反应10小时。20小时后将产物取出,进行精制和干燥,得到PEG-HA-6聚合物。
【实施例7】
(用红外光谱测量聚合物的缩合率)
PEG-HA-5与PEG-HA-6的PEG缩合率是由红外光谱定量测得。主要测量PEG在2870cm-1与透明质酸在1025cm-1的两处红外吸收峰,制备多种不同比例的PEG与透明质酸的混合物并测定混合物的红外光谱(2870cm-1の強度/1025cm-1)与两种高分子物质的组成比例作检量线。然后,将PEG-HA-5与PEG-HA-6的红外光谱结果代入检量线中,算出缩合率。红外分光光度计使用高速红外光谱(FTIR)成像系统(型号:Spectrum100FT-IR/Spotlight400,PerkinElmer Japan Co.,Ltd)算出PEG-HA-5的缩合率为0.27;PEG-HA-6为0.29缩合率。
【实施例8】
(PEG-graft-HA抗酶降解)
用PEG-HA-5、PEG-HA-6、Q社产具有抗酶降解性能的透明质酸、以及HA(FCH-SU 9)作为对比物的进行酶分解抑制实验。各实验试剂均用0.15mole%PBS溶解成2WT%溶液,向其中添加2units/mg HA透明质酸酶(Hyaluronidase“AMANO”,和光纯药株式会社),在0、8、16、24、32小时5个采样点采样。采样后根据试剂分解后产生的低分子量,算出分解率,绘制图4如下。本实验通过测量溶液中被分解的低分子的量,来测算透明质酸的分解。
PEG-HA-5和PEG-HA-6与透明质酸,以及市面上贩卖的具有抗酶降解性能的透明质酸比,具有更高的抗酶降解作用。
Claims (16)
1.由含有PEG-羧基的高分子聚合物组成的DDS载体。
2.权利要求1所述用作DDS载体的含羧基聚合物为含有羧基的多糖类。
3.权利要求2所述用作DDS载体的含有羧基的多糖为透明质酸。
4.权利要求1~3中任一项所述的DDS载体是由羧基和PEG被酯键连接而成。
5.权利要求1~3中任一项所述的DDS载体是由羧基和PEG被酰胺键连接而成。
6.权利要求1~5中任一项所述的是含有DDS载体的注射剂。
7.权利要求1~5中任一项所述的是含有DDS载体的口服剂。
8.权利要求1~5中任一项所述的是含有DDS载体的体内嵌入式制剂。
9.权利要求1~5中任一项所述的是含有DDS载体的经皮吸收制剂。
10.权利要求1~3中任一项所述的是含有DDS载体的化妆品。
11.权利要求1~5中任一项所述的是含有DDS载体的微针制剂。
12.由胰岛素和PEG-羧基多糖聚合物构成的缓释胰岛素制剂。
13.由艾塞那肽和PEG-羧基多糖聚合物构成的艾塞那肽缓释制剂。
14.制备工艺为在酸性条件下,使PEG与含有羧基的多糖类进行缩合反应的PEG-羧基多糖聚合物的制备方法。
15.制备工艺为在含三嗪类缩合剂的环境中,使胺化的PEG与含有羧基的多糖类进行缩合反应的PEG-羧基多糖聚合物的制备方法。
16.权利要求15所述的制造方法,其中使用的三嗪类缩合剂是DMTMM。
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KR20180030033A (ko) | 2018-03-21 |
WO2017010518A1 (ja) | 2017-01-19 |
EP3323429A1 (en) | 2018-05-23 |
CN117503939A (zh) | 2024-02-06 |
AU2016293784A1 (en) | 2018-01-25 |
AU2016293784B2 (en) | 2021-11-11 |
JP2017019791A (ja) | 2017-01-26 |
JP6560166B2 (ja) | 2019-08-14 |
EP3323429A4 (en) | 2019-02-27 |
US20180193465A1 (en) | 2018-07-12 |
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