355117-38-3Relevant articles and documents
Liquid chromatographic resolution of amino acid esters of acyclovir including racemic valacyclovir on crown ether-based chiral stationary phases
Ahn, Seong Ae,Hyun, Myung Ho
, p. 268 - 273 (2015)
Valacyclovir, a potential prodrug for the treatment of patients with herpes simplex and herpes zoster, and its analogs were resolved on two chiral stationary phases (CSPs) based on (3,3′-diphenyl-1,1′-binaphthyl)-20-crown-6 covalently bonded to silica gel. In order to find out an appropriate mobile phase condition, various mobile phases consisting of various organic modifiers in water containing various acidic modifiers were applied to the resolution of valacyclovir and its analogs. When 30% acetonitrile in water containing any of 0.05 M, 0.10 M, or 0.15 M perchloric acid was used as a mobile phase, valacyclovir and its analogs were resolved quite well on the two CSPs with the separation factors (α) in the range of 2.49～6.35 and resolutions (RS) in the range of 2.95 ～ 12.21. Between the two CSPs, the CSP containing residual silanol protecting n-octyl groups on the silica surface was found to be better than the CSP containing residual silanol groups.
Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir
Yang, Chun,Gao, Hongwu,Mitra, Ashim K.
, p. 617 - 624 (2001)
The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate β-ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37°C. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37°C. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate β-ester. The stability of all three esters decreased with increasing pH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p 1%). L-Aspartate β-ester was absorbed to the extent of ～8% over 90 min of perfusion at an initial drug concentration of 100 μM. Nasal absorption of L-aspartate β-ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate β-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system.
Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability
Chen, Yong,Alberti, Ingo,Kalia, Yogeshvar N.
, p. 103 - 113 (2016/01/15)
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 (QDEP,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, QDEP,TOTAL = QDEP,ACV + QDEP,ACV-X. QDEP,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.
