Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability

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• 作者：Yong Chen ; Ingo Alberti ; Yogeshvar N. Kalia ; ^{yogi.kalia@unige.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Aciclovir ; Prodrug ; Stability ; Iontophoresis ; Skin ; Skin retention ; Bioconversion
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：99
• 期：Complete
• 页码：103-113
• 全文大小：923 K

文摘

The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV = aciclovir and X = Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by ¹H NMR and high resolution mass spectrometry. Analytical methods using HPLC–UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8 h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2 h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2 h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm² for 2 h led to modest ACV skin deposition (Q_DEP,ACV) of 4.6 ± 0.3 nmol/cm². In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, Q_DEP,TOTAL = Q_DEP,ACV + Q_DEP,ACV-X. Q_DEP,TOTAL for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 ± 44.0, 358.8 ± 66.8, 434.1 ± 68.2, 249.8 ± 81.4, 156.1 ± 76.3, 785.9 ± 78.1 nmol/cm², respectively. The extent of bioconversion of ACV-X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV-X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a function of current density (0.125, 0.25 and 0.5 mA/cm²); the effect of duration of current application (5, 10, 30, 60 and 120 min) was evaluated using ACV-Arg and ACV-Ile. Iontophoresis of ACV-Arg and ACV-Ile at 0.25 mA/cm² for only 5 min resulted in the deposition of appreciable amounts of ACV (36.4 ± 5.7 nmol/cm² and 40.3 ± 6.1 nmol/cm², respectively), corresponding to supra-therapeutic average concentrations in skin against HSV-1 or HSV-2. The results demonstrated that cutaneous bioavailability of ACV could be significantly improved after short-duration iontophoresis of ionizable, biolabile ACV-X prodrugs.