CN101780281B - N-精氨酸壳聚糖作为透皮吸收促进剂的应用 - Google Patents
N-精氨酸壳聚糖作为透皮吸收促进剂的应用 Download PDFInfo
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- CN101780281B CN101780281B CN2010100172137A CN201010017213A CN101780281B CN 101780281 B CN101780281 B CN 101780281B CN 2010100172137 A CN2010100172137 A CN 2010100172137A CN 201010017213 A CN201010017213 A CN 201010017213A CN 101780281 B CN101780281 B CN 101780281B
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- arginine
- chitosan
- transdermal
- solution
- insulin
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Abstract
本发明属于生物医药领域，确切的说是一种壳聚糖衍生物-N-精氨酸壳聚糖作为透皮吸收促进剂的应用。本发明的有益成果在于提供了一种结构较为简单、可生物降解，具有良好促进大分子药物以及难渗透性药物透皮吸收的壳聚糖衍生物。
Description
技术领域：
本发明属于生物医药领域，确切地说它是关于一种N-精氨酸壳聚糖在促进药物透皮吸收中的应用。
背景技术：
药物透皮给药系统具有可以避免药物在胃肠道内的降解和肝脏首过作用以及随时给药或随时撤销给药等独特优点，因此自从其问世以来，就得到了不断的完善和迅猛的发展。但由于许多药物的透皮速率以及透皮药量很低，不能满足临床治疗要求，因此提高药物的透皮给药成为了开发透皮给药系统的关键。解决这个问题的常用方法有药剂学方法、化学方法和物理学方法等，而使用透皮吸收促进剂是应用最多的一种药剂学方法。
透皮促进剂分为化学合成透皮促进剂和天然透皮促进剂。近年来，天然透皮吸收促进剂以起效快、效果好、副作用小等优点，正日益引起人们的重视。因此，从天然产物中寻找透皮吸收促进剂，具有广阔的应用前景。
壳聚糖由甲壳质经脱乙酰基而得，具有良好的成膜性、生物可降解性、生物相容性以及一定的抗菌、抗肿瘤性能，被广泛应用于医药、食品、化工、环保等行业，素有万能多糖的美誉。壳聚糖由于其结构上的氨基和羟基而具有高化学反应活性，且易于被一些化学试剂修饰，因此对壳聚糖进行化学改性而使其具有新功能的研究屡见报道。一些研究表明，N-三甲基壳聚糖以及巯基化壳聚糖应用于微粒给药系统中具有一定的促进胰岛素等口服、粘膜给药吸收的作用；Wen He等还报道了N-三甲基壳聚糖具有促进睾酮透皮吸收的作用(Wen He，Xianxi Guo，Mian Zhang.Transdermal permeation enhancement of N-trimethyl chitosan fortestosterone.International Journal of Pharmaceutics 2008，356：82-87)。
近年来，一些具有细胞膜穿透能力的多肽例如TAT peptide、MPG、PEP-1、penetratin、octaarginine等逐渐成为关注的焦点，它们可高效穿过细胞膜而细胞膜却完好无损。这些天然的或人工合成的多肽能够携带各种分子或纳米载体进入各种细胞膜，被称之为穿膜肽。其中有些细胞穿膜肽为带有正电荷的长短不一的多肽片段，这些多肽片段多为精氨酸等碱性氨基酸残基。
由于精氨酸为碱性带正电的水溶性氨基酸，在壳聚糖主链上引入精氨酸基团，可以明显改善壳聚糖的水溶性，此外，由于的壳聚糖的2位氨基带有正电荷，能与荷负电的细胞膜结合，打开细胞间的紧密连接，同时精氨酸的荷正点胍基基团的存在，可以与荷负电的亲水性小分子药物，以及荷负电的大分子药物如胰岛素、肝素等产生静电结合，使其能有效地穿透细胞膜。利用以上所述的壳聚糖和穿膜肽的这些特点，合成而得的N-精氨酸壳聚糖衍生物，不仅可以明显改善壳聚糖的水溶性，而且我们还发现其具有良好的促进透皮吸收的作用。
目前有关精氨酸壳聚糖衍生物作为药用的报导不多，LiuWG等利用十六烷基修饰的壳聚糖制备而成的纳米粒用于基因载体的研究(LiuWG，Yao KD，Liu QG.Formation of a DNA/N-Dodecy-lated chitosan complex and salt-induced gene delivery[J].J Appl Polym Sci，2001，82(14)：3391-33951.)；刘文广有利用精氨酸能与血液中丝氨酸酶作用，与壳聚糖形成缀合物后作为抗凝血材料使用的专利报导(发明专利：ZL03144230.7)；朱敦皖等利用精氨酸壳聚糖作为基因载体，用于提高基因转染效率(朱敦皖等，精氨酸修饰壳聚糖提高基因转染效率的研究.科学通报[J]，2007，52(18)：2199-2205.)。但利用精氨酸与壳聚糖的衍生物作为透皮促渗剂的研究国内外均未见文献与专利报导。
发明内容：
本发明的目的旨在提供一种新型透皮吸收促进剂，其以壳聚糖为骨架，侧链氨基上修饰精氨酸，作为一种透皮促渗剂，将其应用于透皮给药上，具有极好的促进药物透皮吸收的效果。
一种新型的透皮吸收促进剂，由下列通式表示：
所述的透皮吸收促进剂，其主要特征为：壳聚糖分子量为3000～1000000D，脱乙酰度为55-92％，精氨酸取代度为0.5～90％。
所述的透皮吸收促进剂，主要加入各种药物的透皮给药制剂中作为吸收促进剂使用，也可与药物形成组合物。
所述的精氨酸及其盐为L-精氨酸、D-精氨酸、DL-精氨酸、L-精氨酸盐酸盐、D-精氨酸盐酸盐、DL-精氨酸盐酸盐、L-精氨酸硫酸盐、D-精氨酸硫酸盐和DL-精氨酸硫酸盐之中的一种。
所述的药物首选蛋白多肽类大分子药物以及难以渗透皮肤或粘膜的药物。蛋白多肽类大分子药物优选胰岛素，可以是生长激素、脑啡肽、干扰素、催产素、疫苗、单克隆抗体、DNA、sRNA。难渗透性药物优选阿德福韦、盐酸苯环壬酯、茶苯海明、苯海拉明，可以是盐酸二甲双胍、盐酸阿霉素、硫酸长春新碱、盐酸小檗碱、盐酸柔红霉素，盐酸拓扑替康、阿昔洛韦、更昔洛韦、阿米洛利、阿替洛尔、阿莫西林、头孢拉定、环丙沙星、甲氨蝶呤、两性霉素B、丝裂霉素、新霉素、粘菌素、喜树碱类(喜树碱、10-羟基喜树碱、9-硝基喜树碱、SN-38等)、紫杉醇、多西紫杉醇、替尼泊苷、依托泊甙、环孢素A、柔红霉素、冬凌草素、藤黄酸、三尖杉酯、高三尖杉酯、灯盏花素、银杏内酯、水飞蓟素、阿德福韦酯、恩替卡韦。
所述的透皮制剂，可以是O/W型软膏剂、W/O型软膏剂、水凝胶软膏剂、膜控型、基质型、骨架型透皮给药系统等。
所述的透皮吸收促进剂，在透皮制剂中的使用剂量以及与药物形成组合物的含量为0.5-90％。
以下通过非限定性实施例进一步详细说明本发明，本发明的保护范围，不局限于此。
具体实施方式：
实施实例1：N-精氨酸壳聚糖促进阿德福韦透皮吸收的实验研究
1、N-精氨酸壳聚糖的合成
(一)精氨酸侧链氨基的BOC保护：称取精氨酸5克溶于200ml去离子水中，另称取4克Boc酸酐溶于200ml四氢呋喃，将溶有Boc酸酐的四氢呋喃溶液加入精氨酸的水溶液中，搅拌均匀，滴加1mol/L的NaOH溶液调节pH值至9-10，室温搅拌反应24小时，将反应液置旋转蒸发仪上除去四氢呋喃-水混合液，得N-叔丁氧羰基精氨酸，取200ml去离子水将其溶解。
(二)N-精氨酸壳聚糖的合成：称取脱乙酰化度90％、分子量10000的壳聚糖10克，加入到1％的冰醋酸水溶液中，室温搅拌12小时，使壳聚糖完全溶解，加入1.4克N-羟基-丁二酰亚胺和6克1-乙基-3-(3-二甲胺丙基)碳二亚胺以及N-叔丁氧羰基精氨酸水溶液，室温下搅拌反应48小时后，去离子水透析48小时，冷冻干燥得最终产物，元素分析计算取代度为6％。
FTIR：1615.97cm-1(精氨酸胍基)，1526.23cm-1(精氨酸与壳聚糖反应生成的酰胺键的吸收峰)，1149cm-1(精氨酸C-C-N键的非对称伸缩振动峰)，1072.54cm-1(壳聚糖吡喃环上的C-O伸缩振动)。
元素分析法结合核磁共振法测得其精氨酸取代度为6％。
(三)不同取代度壳聚糖衍生物的合成：将精氨酸的用量按比例增加，其它合成步骤同(一)和(二)，可得到不同取代度的N-精氨酸壳聚糖。
2、透皮实验
样品溶液的配制：称取180mg阿德福韦溶于52ml 0.1mol/L的HCl溶液中，将此药物溶液平均分为6份；分别取精氨酸、壳聚糖、精氨酸与壳聚糖的衍生物以及精制纯化后的N-精氨酸壳聚糖180mg四份分别溶于阿德福韦水溶液中，以1mol/L的NaOH调节溶液9pH值至7，加蒸馏水至全量，配置得到含阿德福韦浓度为0.3％，N-精氨酸壳聚糖浓度为2％的溶液。
透皮实验：取体重为18～22g雄性小鼠，断颈处死，剃净腹部体毛，取无损伤皮肤。在表面皿上除去皮下脂肪，用生理盐水冲洗皮肤内表面。-4℃冷藏保存，48小时内使用。将皮肤固定在Franz扩散池的上、下两室之间，角质层朝上，接受液为0.9％的生理盐水溶液，释放液为样品溶液3ml，将装置置于(32±0.5)℃恒温水浴中，开动搅拌(200r·min-1)，分别于0.5，1，2，4，6，8，10，12h取样1mL，同时补加相同温度等体积新鲜接受液。样品用0.22um微孔滤膜过滤，取样品续滤液1ml用流动相稀释后进行HPLC分析，并计算药物的累积渗透量(Qn)，平行操作三份取平均值。
3、实验结果与数据
采用不同分子量壳聚糖、壳聚糖与精氨酸混合物以及N-精氨酸壳聚糖作为促渗剂，12小时阿德福韦累积透皮渗透量数据结果如表1所示。结果表明与单独精氨酸、壳聚糖以及精氨酸与壳聚糖的物理混合物作为促渗剂相比，不同分子量，不同取代度的N-精氨酸壳聚糖均可大幅度的提高阿德福韦的透皮吸收。
表1不同促渗剂对阿德福韦透皮吸收的影响
实施实例2胰岛素
1、N-精氨酸壳聚糖的合成：同实施例1。
2、透皮实验
样品溶液的配制：称取30mg胰岛素溶于18ml(0.1mol/L)的HCl溶液中，将此药物溶液平均分为6份，以1mol/L的NaOH调节溶液9pH值至7，加蒸馏水至全量，分别取精氨酸、聚糖、精氨酸与壳聚糖的衍生物以及精制纯化后的N-精氨酸壳聚糖60mg四份溶于以上溶液中，配置得到含精氨酸、聚糖、精氨酸与壳聚糖的衍生物以及N-精氨酸壳聚糖浓度为2％的胰岛素溶液。
透皮实验：取以上配制好的溶液进行透皮实验，实验方法同实施例1。
3、实验结果与数据
采用不同分子量壳聚糖、壳聚糖与精氨酸混合物以及N-精氨酸壳聚糖作为促吸收剂，12小时胰岛素累积透皮渗透量数据结果如表2所示。结果表明与单独精氨酸、壳聚糖以及精氨酸与壳聚糖的物理混合物作为促渗剂相比，不同分子量的N-精氨酸壳聚糖可大幅度的提高胰岛素的透皮吸收。
表2不同促渗剂对胰岛素透皮吸收的影响
Claims (1)
1.一种N-精氨酸壳聚糖用作药物透皮吸收促进剂的用途，其特征在于：所述N-精氨酸壳聚糖是分子量为10000D、脱乙酰度为90％的壳聚糖，其侧链氨基为精氨酸取代，取代度为6％，所述药物为胰岛素和阿德福韦酯，其中胰岛素与所述N-精氨酸壳聚糖的质量比为1∶2，阿德福韦酯与所述N-精氨酸壳聚糖的质量比为1∶1。
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