Tailored dual release of retinol and salicylic acid from salicylate-based poly(anhydride-ester) microspheres with tunable degradation profiles.

Retinol and salicylic acid are potent bioactive agents commonly used to treat skin pathologies such as acne, psoriasis, and photodamage. Their combined use offers synergistic therapeutic benefits. However, effective delivery of retinol remains challenging due to its poor aqueous solubility and rapid degradation under physiological conditions. In this study, a dual-delivery microsphere platform based on salicylic acid-derived poly(anhydride-ester)s (SAPAEs) was designed to co-release retinol and salicylic acid in a controlled and pH-responsive manner. Four SAPAE compositions with distinct degradation kinetics were synthesized via melt-condensation polymerization, incorporating different ratios of anhydride and ester linkages through copolymerization. Microspheres with reproducible size (∼10 µm) were formulated using an oil-in-water solvent evaporation method, achieving high salicylic acid loadings (54-77 wt%) via polymer composition and retinol loadings of 0.5-1.5 wt% through physical encapsulation. Thermodynamic predictions of retinol-polymer affinity showed reasonable agreement with experimental retinol loading results. Kinetic models applied to the release profiles confirm a surface-erosion mechanism for polymer degradation and subsequent salicylic acid release, while retinol release was mostly driven by diffusion. Faster release of both bioactive compounds were observed in basic solution. Among the formulations tested, the copolymer containing p-phenylenediacetic acid (PA) as the co-monomeric unit (SAA-co-PA) demonstrated the most controlled dual-release profile, with minimal retinol burst and sustained salicylic acid release. This tunable SAPAE-based microsphere platform offers a promising strategy for synergistic controlled delivery of multiple bioactive for skin pathologies and could be extended to other topical applications.