Liposomal Gel for enhancing topical efficacy of timolol maleate against proliferating superficial infantile hemangiomas

Conventional timolol maleate (TM) eye drops are limited by low transdermal bioavailability and short dermal residence time for the treatment of superficial infantile hemangioma (IH). To address this, a novel 0.5% TM-loaded liposomal gel (TM-lipogel) was developed by embedding optimized liposomes within a carbomer gel matrix. The TM-liposomes exhibited a desirable particle size of 139.5 ± 2.1 nm, a polydispersity index (PDI) of 0.051, a zeta potential of −38.7 mV, and an encapsulation efficiency of 64.76 ± 3.2%. Ex vivo permeation studies revealed a 1.9-fold increase in cumulative transdermal delivery compared to the TM-gel, and 4-fold compared to the TM solution ( p  < 0.05). Furthermore, confocal laser scanning microscope imaging revealed that TM-lipogel achieved a penetration depth of 400 μm, while the TM-gel and TM-eyedrop only reached 200 μm and 75 μm, respectively, highlighting the superior penetration of the liposomal gel. In a murine xenograft hemangioma model, 0.5% TM-lipogel achieved superior tumor regression (81.09%, p  < 0.01 vs. control) compared to 0.5% TM-eyedrop (29.85%) and 0.5% TM-gel (61.69%) by simultaneously downregulating HIF-1α, VEGF, MMP-9 and eNOS. Critically, the optimized formulation exhibited no skin irritation and no systemic toxicity. These findings highlight that the TM-lipogel provides enhanced transdermal delivery with deeper tissue penetration, representing a highly effective and safe transdermal strategy for IH therapy.