Ester derivatives of phyllohydroquinone effectively deliver the active form of vitamin K1 topically, owing to their non-photosensitivity
Ester derivatives of phyllohydroquinone effectively deliver the active form of vitamin K1 topically, owing to their non-photosensitivity
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DOI：
10.1016/j.ejps.2020.105519
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发表时间：
2020-12-01
影响因子：
4.6
通讯作者：
Takata, Jiro
中科院分区：
文献类型：
--
作者：
Goto, Shotaro;Setoguchi, Shuichi;Takata, Jiro
叶绿醌（PK）的局部应用对皮肤有益;然而，由于其光敏特性（如光降解和光毒性），其局部使用在欧洲受到限制。我们评估了叶氢醌（PKH）的酯衍生物（PK的活性形式）用于局部应用以克服PK的上述问题的适用性。我们使用PKH衍生物PKH-1，4-双-N，N-二甲基甘氨酸盐酸盐（PKH-DMG）和PKH-1，4-双-半琥珀酸盐（PKH-SUC）进行我们的研究。光稳定性通过测量用人造日光和多波长光照射后的残留浓度来确定。通过测量药物诱导的单线态氧和细胞内活性氧（ROS）的产生以及人表皮角质形成细胞系（HaCaT）的细胞活力来评估紫外线A（UVA）照射后的光毒性。通过测量PK环氧化物（PKO）水平来评估PKH向HaCaT细胞的递送。PKH衍生物显示出比PK更高的光稳定性。UVA照射后，PK诱导高单线态氧水平和细胞内ROS的产生，并降低细胞活力，而PKH衍生物没有表现出任何影响。PKH衍生物增加细胞内PKO水平。PKH-DMG和PKH-SUC治疗后的AUC（PKO（0-72 h））值分别是PK治疗后的0.741倍和22.9倍。总之，PKH衍生物作为PKH前药，适用于局部应用，而不需要特殊的避光保护。
Topical application of phylloquinone (PK) is beneficial to the skin; however, its topical use is limited in Europe owing to its photosensitive properties such as photodegradation and phototoxicity. We evaluated the suitability of ester derivatives of phyllohydroquinone (PKH), the active form of PK, for topical application to overcome the abovementioned problems of PK. We used the PKH derivatives PKH-1,4-bis-N,N-dimethylglycinate hydrochloride (PKH-DMG) and PKH-1,4-bis-hemisuccinate (PKH-SUC) for our studies. Photostability was determined by measuring the residual concentration after irradiation with artificial sunlight and multi-wavelength light. Phototoxicity after ultraviolet A (UVA) irradiation was assessed by measuring drug-induced singlet oxygen and intracellular reactive oxygen species (ROS) generation, and cell viability of a human epidermal keratinocyte cell line (HaCaT). Delivery of PKH into HaCaT cells was assessed by measuring PK epoxide (PKO) levels. The PKH derivatives showed higher photostability than PK. After UVA irradiation, PK induced high singlet oxygen levels and intracellular ROS generation, and reduced cell viability, whereas the PKH derivatives showed no effects. The PKH derivatives increased intracellular PKO levels. AUC(PKO(0-72 h)) values after PKH-DMG and PKH-SUC treatments were 0.741- and 22.9-fold higher than that after PK treatment, respectively. In conclusion, PKH derivatives act as PKH prodrugs and are suitable for topical application without the need for special protection from light.