【摘要】 目的:本文以α-萜品醇(TER)为先导化合物与直链脂肪酸通过酯化反应合成系列萜品醇酯[丁酸萜品醇酯(TERC4)、己酸萜品醇酯(TER-C6)、庚酸萜品醇酯(TER-C7)、癸酸萜品醇酯(TER-C10)、十二酸萜品醇酯(TER-C12)、十四酸萜品醇酯(TER-C14)、十八酸萜品醇酯(TER-C18)、油酸萜品醇酯(TER-dC18)],并考察α-萜品醇酯对格列美脲(GMPD)的促渗透活性及优选促透剂的皮肤刺激性。方法:采用水平扩散池以离体家兔皮肤为屏障进行体外透过试验,系统考察了α-萜品醇酯类衍生物及常用促透剂[L-薄荷醇(M)、月桂氮艹卓酮(azone)、N-甲基吡咯烷酮(NMP)]对GMPD的促渗活性并确定最优处方。采用家兔自身对照,单次/多次给药皮肤刺激性实验及组织学评价法考察TER及TER-C14对家兔皮肤的刺激性。结果:在肉豆蔻酸异丙酯(IPM)溶液中,所有促渗剂均有显著的促透作用(P <0. 05); TER-C14、TER-dC18的促渗作用均显著高于TER(P<0. 05);而制成压敏胶分散型(DIA)贴剂后,仅TER、TER-C6、TER-C14、TER-dC18及M均有显著促渗作用(P <0. 05),当5%TER-C14与5%M联合应用时,GMPD的24 h累积透过量是空白组的3. 95倍。皮肤刺激性实验及组织学评价结果均表明TER和TER-C14均无明显的刺激性。结论:α-萜品醇酯衍生物对GMPD有显著促透活性且皮肤刺激性低,可作为促透剂候选化合物进一步深入研究。更多还原

【Abstract】 Objective: To synthesize a series of terpene alcohol esters [2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl butanoate( TER-C4),2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl hexanoate( TER-C6),2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl heptanoate( TER-C7),2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl decanoate( TER-C10),2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl dodecanoate( T-C12),2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl tetradecanoate( TER-C14),2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl stearate( TER-C18) and( E)-2-( 4-methylcyclohex-3-en-l-yl) propan-2-yl octadec-9-enoate( TER-dC18) ] by esterification of alpha-terpene alcohols( TER) with straight-chain fatty acids,and investigate the penetration enhancement of alpha-terpene alcohol esters on glimepiride( GMPD) and the skin irritation of the optimized penetration enhancers. Methods: The in vitro permeation studies of GMPD were conducted in side-by-side diffusion cells,the penetration effects of O-acylterpineol,l-menthol( M),azone and N-methylpyrrolidone( NMP) on the permeation behavior of GMPD were also investigated,and then the optimal formulation was determined.Histological experiments and skin irritation assays were also applied to study the irritation of TER and TER-C14 by the self-contrasted method in rabbits. Results: The results of penetration experiment showed that almost all the enhancers had enhancing effects on the penetration of GMPD in isopropyl myristate( IPM) solution( P < 0. 05),and TER-C14 and TER-dC18 showed obviously higher penetration enhancement than that of TER( P < 0. 05). While in the DIA patches,only TER,M,TER-C6 and TER-dC18 could promote the penetration of GMPD. The combinations of 5% TER-C14 and 5% M could provide the highest penetration amounts of GMPD( 3. 95-fold) when compared to the control group( P < 0. 05). The skin simulative experimental results showed that TER and TER-TET had no obvious skin irritation. Conclusion: O-Acylterpineol derivatives with low skin irritation have significant promoting effects on the penetration of GMPD,which indicates that O-acylterpineol needs to be further studied in future as a candidate enhancer.更多还原