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超饱和体系改善阿昔洛韦脂肪酸酯前体药物的透皮递送
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| 篇名： | 超饱和体系改善阿昔洛韦脂肪酸酯前体药物的透皮递送 |
| TITLE： | Improvement of Transdermal Delivery of Aciclovir Aliphatic Ester Prodrugs by Using Supersaturated System |
| 摘要： | 目的：制备亲脂性阿昔洛韦（ACV）前体药物的超饱和体系，增加ACV的皮肤生物利用度。方法：采用酸酐酰化法合成ACV的乙酸酯（ACV-Ace）、丁酸酯（ACV-But）和己酸酯（ACV-Hex）等3种ACV前体药物。使用核磁共振氢谱、高分辨质谱确证ACV及3种ACV前体药物的结构；采用超高效液相色谱-三重四极杆串联质谱法测定ACV及3种ACV前体药物的浓度，并计算其在不同体积分数的丙二醇-水溶液中的饱和溶解度，筛选出超饱和体系形成潜力最大的化合物。通过共溶剂法制备该化合物的超饱和体系，并采用光学显微镜观察羟丙基甲基纤维素E3（HPMCE3）对其物理稳定性的影响。采用立式Franz扩散池研究超饱和度（DS）和HPMCE3对该超饱和体系在离体猪皮上作用1h后药物皮肤蓄积量的影响，采用冷冻层切-分层定量法测定使用上述超饱和体系和上市阿昔洛韦乳膏1h后药物在离体猪皮中的分布情况。结果：3种ACV前体药物均被成功合成。建立的定量方法符合生物样品分析要求。在3种前体药物中，ACV-Hex显示出最小的水饱和溶解度（[0.5±0.0）mmol/L]和最大的丙二醇饱和溶解度（[53.4±14.2）mmol/L]，具备形成具有较高DS的超饱和体系的潜力。在10％丙二醇-水体系中，HPMCE3的加入可保证DS不超过4的ACV-Hex超饱和体系在1h内保持物理稳定。含有HPMCE3的DS为4的ACV-Hex超饱和体系作用1h后的总皮肤蓄积量（ACV+ACV-Hex）高于DS＜4或不含HPMCE3的ACV-Hex超饱和体系作用后的总皮肤蓄积量；另外，上述超饱和体系渗透进入基底表皮层（皮肤厚度为100～160μm）的ACV量显著高于上市药品阿昔洛韦乳膏（P＜0.05）。结论：ACV的亲脂性前体药物ACV-Hex可在HPMCE3存在下，于10％丙二醇-水体系中形成稳定的DS为4的超饱和体系；其作用于离体皮肤1h后可在基底表皮层蓄积较高浓度的ACV，可能对局部治疗单纯疱疹病毒皮肤感染具有一定价值。 |
| ABSTRACT： | OBJECTIVE：To prepare supersaturated system of lip ophilic aci clovir（ACV）prodrug，and to increase the cutaneous bioavailability of ACV. METHODS ：Three prodrugs of ACV were synthesized by anhydride acylation ，i.e. aciclovir acetate （ACV-Ace），butyrate（ACV-But）and hexanoate （ACV-Hex）. The structures of ACV and three ACV prodrugs were confirmed by 1H-NMR and HRESI-MS ；the concentrations of ACV and three ACV prodrugs were determined by UPLC-triple quadrupole tandem mass spectrometry ，and saturated solubility of them in different volume fractions of propylene glycol-water solution was calculated. The compound with the greatest potential of form supersaturated system was screened out. The supersaturated system of that compound was prepared by co-solvent method. The effect of hydroxypropyl methylcellulose E 3 （HPMC E 3） on its physical stability was observed by light microscope. Vertical Franz diffusion cells were used to study the effects of degree of supersaturation （DS）and HPMC E 3 on the deposited amount of drug in the excised porcine skin after using the supersaturated system for 1 h. The distribution of ACV in the excised porcine skin was determined by frozen slicing stratified quantitative method after using the supersaturated system and marketed aciclovir cream for 1 h. RESULTS ：Three ACV prodrugs were successfully synthesized. The established quantification methods met the requirements of biological sample analysis. Among all of the three ACV prodrugs ， ACV-Hex showed the lowest saturated solubility in water [ （0.5±0.0）mmol/L] a nd the highest saturated solubility in propylene glycol [（53.4 ± 14.2）mmol/L]，which made it potentially feasible to form supersaturated system with high DS. In 10％propylene glycol-water system ，the addition of HPMC E 3 163.com enabled ACV-Hex supersaturated systems ，with DS no morethan 4，to maintain physical stability within 1 h. The total deposited amount （ACV + ACV-Hex ） in skin after the application of ACV-Hex supersaturated system with DS of 4 for 1 h was higher than that after the application of ACV-Hex supersaturated system with DS less than 4 or without HPMC E 3. In addition ，the concentration of ACV in the basal epidermis （skin thickness was 100-160 mm）by supersaturated system was significantly higher than that of the marketed aciclovir cream （P＜0.05）. CONCLUSIONS：ACV-Hex，the lipophilic prodrug of ACV ，can form stable supersaturated system with DS of 4 in 10％ propylene glycol-water system in the presence of HPMC E 3. High concentration of ACV could be accumulated in the basal epidermis after the skin was exposed to supersaturated system for 1 h，which may be valuable for local treatment skin infection of herpes simplex virus . |
| 期刊： | 2021年第32卷第16期 |
| 作者： | 周烨，张琴，顾悦，金怡兰，许晓乐，陈勇 |
| AUTHORS： | ZHOU Ye，ZHANG Qin，GU Yue，JIN Yilan，XU Xiaole ，CHEN Yong |
| 关键字： | 阿昔洛韦；亲脂性前体药物；超饱和体系；皮肤感染；单纯疱疹病毒 |
| KEYWORDS： | Aciclovir；Lipophilic prodrug ；Supersaturated system ；Skin infection ；Herpes simplex virus |
| 阅读数： | 342 次 |
| 本月下载数： | 9 次 |
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