Chang Shih-Jen, Wang Huiyuan, Chen Jialin, Chen Qianyi, Chang Lei, Huang Yongzhuo, Qiu Yajing, Lin Xiaoxi
Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Pharmaceutics. 2022 Aug 1;14(8):1607. doi: 10.3390/pharmaceutics14081607.
Infantile hemangiomas (IH) leave sequelae after involution. Topical application of timolol maleate (TM) is the mainstream treatment for superficial lesions but is limited by its low penetrable properties. We aimed to develop a superior skin permeation drug while maintaining the therapeutic properties of timolol. We predict that this drug will promote the involution of thick and deep IH lesions and avoid sequelae. We chemically modified drug structure to prepare butyryl timolol maleate (BT) prodrug and conducted in vitro and in vivo toxicity evaluations of BT with rat dorsal skin and normal skin cells. Skin permeation and absorption comparisons of TM and BT were conducted using rat and porcine skin models. Conversion efficiency of BT to timolol was also tested on human skin ex vivo. BT did not cause skin irritation on rat dorsal skin and exhibited low cytotoxicity overall. BT exhibited superior skin permeation ability compared with that of TM, whilst maintaining a low systemic absorbance. Further, BT was converted to timolol in human skin in a time-dependent manner. Noticeably, timolol accumulation in the skin from BT was higher than that from TM. Finally, BT demonstrated similar biocompatibility with TM in the IH tumor. BT enhances local delivery of timolol and its skin permeation. Using BT, we could eliminate thicker IH lesions that are prone to leave sequelae, and potentially help young children avoid dermal sequelae, disfigurement, and concomitant therapy.
婴儿血管瘤（IH）消退后会留下后遗症。马来酸噻吗洛尔（TM）局部应用是浅表性病变的主流治疗方法，但受其低渗透性的限制。我们旨在开发一种具有更好皮肤渗透性的药物，同时保持噻吗洛尔的治疗特性。我们预测这种药物将促进厚而深的IH病变的消退并避免后遗症。我们对药物结构进行化学修饰以制备马来酸丁酰噻吗洛尔（BT）前药，并对BT与大鼠背部皮肤和正常皮肤细胞进行了体外和体内毒性评估。使用大鼠和猪皮肤模型对TM和BT的皮肤渗透和吸收进行了比较。还在离体人皮肤上测试了BT向噻吗洛尔的转化效率。BT对大鼠背部皮肤未引起皮肤刺激，总体细胞毒性较低。与TM相比，BT表现出更好的皮肤渗透能力，同时全身吸收率较低。此外，BT在人皮肤中以时间依赖性方式转化为噻吗洛尔。值得注意的是，BT在皮肤中积累的噻吗洛尔高于TM。最后，BT在IH肿瘤中表现出与TM相似的生物相容性。BT增强了噻吗洛尔的局部递送及其皮肤渗透性。使用BT，我们可以消除容易留下后遗症的较厚的IH病变，并有可能帮助幼儿避免皮肤后遗症、毁容和伴随治疗。
