An Intelligent Transdermal Formulation of ALA‐Loaded Copolymer Thermogel with Spontaneous Asymmetry by Using Temperature‐Induced Sol–Gel Transition and Gel–Sol (Suspension) Transition on Different Sides

Aqueous solutions of some amphiphilic block copolymers undergo a sol-gel transition upon heating and are thus called thermogels. In the thermogel family, some systems also exhibit a gel-sol (suspension) transition at higher temperatures following the sol-gel transition, which is usually ignored in biomedical applications. Herein, for the first time, a case is reported employing both the sol-gel transition and the gel-sol (suspension) transition, which is found in the development of a transdermal hydrogel formulation containing 5-aminolevulinic acid for photodynamic therapy (PDT) of skin disease. Two poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) triblock copolymers of different block lengths are synthesized. The transition temperatures of the formulation can be easily adjusted to meet the condition of sol-gel transition temperature (T-gel) < room temperature (T-air) < gel-sol (suspension) temperature (T-sol (suspension)) < body temperature (T-body) via changing the blending ratio. Therefore, after applying to skin, formulation of spontaneous asymmetry with a hydrogel outside and a sol (suspension) inside can avoid free flowing and achieve rapid release to ensure an efficient PDT. This study demonstrates such a concept via characterizations of the "block blend" biomaterials and drug release profiles, and also via cell experiments, in vitro permeation, and in vivo transdermal delivery studies.