Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions

Abstract

The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of UqH-10, including a 1-monoester (UqH-1-DMG), 4-monoester (UqH-4-DMG), and 1,4-bis-ester (UqH-DMG), and assessed their physicochemical properties in vitro and in vivo. UqH-DMG spontaneously formed an aqueous micelle solution comprising 20 nm particles at 36.5 °C. Cationic UqH-DMG formed nano-sized (5 nm) mixed-micelles with taurocholic acid. Reconversion of the derivatives to UqH-10 was accelerated in human liver microsomes. The oral bioavailability of UqH-10 after administration of UqH-derivatives or Uq-10 was determined in fasted and postprandial rats secreting normal and high levels of bile, respectively. In fasted rats, plasma UqH-10 after UqH-derivatives administration reached Cmax at 2–3 h and after Uq-10 administration, it remained low. The AUC0-24h of UqH-10 after UqH-derivatives administration was 2–3-fold higher than that after Uq-10 administration. In postprandial rats, the Tmax of UqH-10 after UqH-derivatives administration was an hour earlier than after Uq-10 administration. In conclusion, cationic UqH-derivatives are convenient prodrugs that enhance UqH-10 bioavailability by forming nanosized mixed-micelles with intestinal bile acids.

Evaluation of photostability and phototoxicity of esterified derivatives of ubiquinol‐10 and their application as prodrugs of reduced coenzyme Q10 for topical administration

“…The phototoxicity of Uq‐10 may limit its applicable dosage forms. We previously reported that N,N ‐dimethylglycine ester derivatives of UqH‐10 are stable for oxidation and can act as prodrugs of UqH‐10 in rats after oral administration 22 . In this study, we evaluated whether the ester prodrug strategy of UqH‐10 could avoid the photoinstability and phototoxicity demonstrated by Uq‐10 and UqH‐10.…”

“…Uq‐10 was kindly provided by Kaneka Corporation (Tokyo, Japan). Ubiquinol‐10 1,4‐bis‐ N,N ‐dimethylglycinate hydrochloride (UqH‐DMG), ubiquinol‐10 1‐mono‐ N,N ‐dimethylglycinate hydrochloride (UqH‐1‐DMG), and ubiquinol‐10 4‐mono‐ N,N ‐dimethylglycinate hydrochloride (UqH‐4‐DMG) were prepared and used as previously described 22 . Other chemicals were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan).…”

“…We previously reported that N,N-dimethylglycine ester derivatives of UqH-10 show improved intestinal absorption compared with Uq-10, thus acting as prodrugs of UqH-10 after oral administration. 22 In the present study, we examined whether the use of UqH-10-ester derivatives (UqH derivatives) could prevent the photoinstability and phototoxicity of Uq-10, allowing it to act as an ester prodrug of UqH-10 in HaCaT human keratinocytes.…”

Enhanced Solubility and Antitumor Activity of Annona Squamosa Seed Oil via Nanoparticles Stabilized with TPGS: Preparation and In Vitro and In Vivo Evaluation

“…Obviously, ASSO is insoluble in water, which results in the low bioavailability [19] and greatly limits its wide use. In addition, chemotherapeutic drugs often have serious side effects because they have no selective killing effect on normal cells and tumor cells [20].…”