摘要
目的考察N-三甲基壳聚糖(N-trimethyl chitosan,TMC)作为透皮吸收促进剂的作用,并对其作用机制做初步研究。方法用壳聚糖及碘甲烷为主要原料,合成季铵化程度为60%的TMC,即TMC60,通过1H-NMR确定其季铵化程度。应用衰减全反射傅立叶红外光谱(ATR-FTIR)探讨TMC60对角质层角蛋白的作用。以月桂氮酮为阳性对照,睾酮为模型药物,考察TMC60对离体皮肤的透皮作用。结果经1H-NMR确定合成得到的TMC60季铵化程度为67.2%。鼠角质层经TMC60处理后,角蛋白的酰胺吸收峰Ⅱ带的峰位从1 538.7 cm-1向低波数位移到1 536.8 cm-1。结合用去卷积方法对酰胺吸收峰Ⅱ进行处理,结果表明,TMC60可使部分角蛋白从α-螺旋型结构向β-折叠型结构和无规则卷曲型结构转变。体外透皮实验中,TMC60组的累积透过量、稳态渗透速率显著大于空白组和月桂氮酮组(P均小于0.05)。结论TMC60有较好的透皮吸收作用,其作用机制与影响皮肤角质层角蛋白结构有关。
Abstract
OBJECTIVE To study the penetration effect of N-trimethyl chitosan(TMC) and its penetration mechanism.METHODS TMC60 was synthesized by a two-step method using chitosan and methyl-iodide.The degree of quaternization of TMC was determined by 1H-NMR.Attenuated total reflection-fourier transform infrared spectroscopy(ATR-FTIR),combined with the technique of deconvolution was used to study the protein conformation of stratum corneum.The 12 h cumulative penetration was determined on mice skin using testosterone as model drug and azone as comparison.RESULTS The quaternization degree of TMC60 was 67.2%.ATR-FTIR spectra showed that amide II absorption peak of keratin shifted from 1 538.7 cm-1 to 1 536.8 cm-1 after the treatment with TMC60.TMC60 changed the keratin conformation from α-helix to β-sheet or random coil leading to a loose keratin structure,therefore reduced the drug transdermal delivery barrier.The cumulative penetration and the steady penetration rate of TMC60 were both higher than the control sample and the sample treated by Azone(P<0.05).CONCLUSION The results suggest that TMC60 is a potential penetration enhancer for transdermal therapeutic systems.The mechanism is correlated with the influence of TMC60 on keratin.
关键词
N-三甲基壳聚糖 /
透皮吸收促进作用 /
衰减全反射傅立叶红外光谱 /
去卷积 /
角蛋白 /
累积透过量
{{custom_keyword}} /
Key words
N-trimethyl chitosan /
penetration enhancement of skin absorption /
attenuated total reflection-fourier transform infrared spectroscopy /
deconvolution /
keratin /
cumulative penetration
{{custom_keyword}} /
何文;张冕;代文兵;吴燕.
N-三甲基壳聚糖透皮吸收促进作用的初步研究[J]. 中国药学杂志, 2006, 41(07): 519-522
HE Wen;ZHNG Min;DI Wen-ing;WU Yn.
Study on Penetration Effect of N-trimethyl Chitosan [J]. Chinese Pharmaceutical Journal, 2006, 41(07): 519-522
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] THANOU M， VERHOEF J C， JUNGINGER H E. Oral drug absorption enhancement by chitosan and its derivatives[J] .Adv Drug Deliv Rev，2001，52：117-126.
[2] HAMMAN J H， STANDER M， KOTZE A F. Effect of the degreee of quaternisation of N-trimethyl chitosan chloride on aborption enhancement：in vivo evaluation in rat epithelia[J] .Int J Pharm，2002，232：235-242.
[3] KOTZE A F， LUESSEN H L， DE BOER A G，et al. Chitosan for enhanced intestinal permeability： prospects for derivatives soluble in neutral and basic environment[J] . Eur J Pharm Sci，1998，7：145-151.
[4] ZHU Y C， LI H Y. Liposome： A sutiable carrier for dermal topical adminisration[J] . Chin J Pharm(中国医药工业杂志)，1998，29（5）：231-235.
[5] ZHOU X Q， XU J， ZHAO X D，et al. Spectroscopic evidence of azone effect on the keratin in mouse stratum corneum[J] .Chem J Chin Univ (高等学校化学学报)，2004，7：1273-1276.
[6] SIEVAL A B， THANOU M， KOTZE A F，et al. Preparation and NMR-characterization of highly substituted N-trimethyl chitosan chloride[J] .Carbohydr Polym，1998，36： 157-165.
[7] THANOU M， KOTZE A F， SCHARRINGHAUSEN T，et al. Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers[J] .J Controlled Release， 2000，64：15-25.
[8] ZHENG J M. Transdermal Drug Delivery System(药物经皮给药新剂型)[M] .Beijing：People Sanitation Press，1997：103-105.
[9] CHEN G S，GONG S J，ZHOU R R，et al. The mechanism of Azone-enhanced estradiol permeation across human skin in vitro[J] . Chin Pharm J(中国药学杂志)，1994，8(29) ：467-469.
[10] VAN DE SANDT J J M， VAN B J A， CAGE S，et al. In vitro predictions of skin absorption of caffeine， testosterone，and benzoic acid：a multi-centre comparison study[J] .Regul Toxicol Pharmacol，2004，39： 271-281.
[11] BI D Z.Pharmacy(药剂学) [M] .Beijing：People Sanitation Press，1998：441.
[12] XU Q W，ZHOU X M，HAO X，et al. Effect of enhancers pretreated skin on percutaneous absorption of diclofenac potassium [J] . Chin J Pharm(中国医药工业杂志)，1998，29（2）：68-70.
[13] A Solvay Pharmaceuticals，Inc.Company.AndroGel[P] .U.S.Patent No.6，503，894.
[14] WU S X，WANG B，ZHAO Q，et al. Penetration study of aceclofenac and diclofenac sodium in vitro[J] .J China Pharm Univ(中国药科大学学报)，2004，35（4）：311-314.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
