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 |
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