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Preformulation of FK506 Prodrugs for Improving Solubility
Author(s) -
Na YoungGuk,
Jun HyeSuk,
Kim Daehee,
Park ByongChul,
Lim SiKyu,
Lee KiHo,
Hwang SungJoo,
Park JeongSook,
Jung SangHun,
Cho CheongWeon
Publication year - 2016
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.10861
Subject(s) - prodrug , solubility , chemistry , differential scanning calorimetry , distilled water , chromatography , organic chemistry , biochemistry , physics , thermodynamics
In order to improve water solubility of a lipophilic drug, tacrolimus ( FK506 ), two prodrugs ( FK506 ‐G or FK506 ‐S) such as FK506‐M32‐LS ‐G ( FK506 ‐G) and FK506‐M32‐LS‐SL ( FK506 ‐S) were synthesized. Two prodrugs ( FK506 ‐G or FK506 ‐S), including FK506 , were characterized by differential scanning calorimetry ( DSC ), X‐ray diffractometry ( XRD ), scanning electron microscopy ( SEM ), enzymatic kinetics, and cytotoxicity. A phase solubility test was conducted in distilled water, and the solubility of two prodrugs ( FK506 ‐G or FK506 ‐S) was measured in various pH values for pH solubility profiles. Most interesting was that FK506 ‐S showed the highest solubility, 866 μg/ mL in water. In vitro enzymatic kinetics of two prodrugs ( FK506 ‐G or FK506 ‐S) in human plasma was evaluated by measuring the decrease of FK506 ‐G or FK506 ‐S as well as the increase of FK506 by HPLC , and FK506 ‐G or FK506 ‐S was metabolized in 1 h in human plasma. Two prodrugs ( FK506 ‐G or FK506 ‐S) including FK506 showed an IC 50 of 336.6 μg/ mL for FK506 , 337.9 μg/ mL for FK506 ‐G, or 480.1 μg/ mL for FK506 ‐S against a conjunctive cell line, Clone 1‐5c‐4 cells. Taken together, FK506 ‐S could be the most optimal prodrug for aqueous preparations based on preformulation data.