超饱和体系改善阿昔洛韦脂肪酸酯前体药物的透皮递送

Improvement of Transdermal Delivery of Aciclovir Aliphatic Ester Prodrugs by Using Supersaturated System

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(HPMC E3)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HPMC E3对该超饱和体系在离体猪皮上作用1 h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1 h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,HPMC E3的加入可保证DS不超过4的ACV-Hex超饱和体系在1 h内保持物理稳定。含有HPMC E3的DS为4的ACV-Hex超饱和体系作用1 h后的总皮肤蓄积量(ACV+ACV-Hex)高于DS<4或不含HPMC E3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HPMC E3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1 h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。

OBJECTIVE:To prepare supersaturated system of lipophilic aciclovir(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 E3(HPMC E3)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 E3 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]and 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 E3 enabled ACV-Hex supersaturated systems,with DS no more than 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 E3.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 E3.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.