HPMA polymers as functional excipients in dermal nanoformulations of imiquimod

A key challenge in topical drug delivery is the inherently low bioavailability of many active compounds within skin tissue. Here, we present the first comprehensive study investigating the impact of biocompatible hydrophilic polymers based on <i>N</i>-(2-hydroxypropyl)methacrylamide (p(HPMA)) on skin barrier properties and its potential to enhance drug permeation. Using imiquimod (IMQ), a model compound known for its poor dermal delivery, we demonstrate that p(HPMA) can significantly influence transport across the skin. To enhance the dermal delivery of IMQ, we investigated three p(HPMA) polymers of varying molecular sizes (5, 20, 80 kg/mol) with very low dispersity. Our initial focus was on the p(HPMA) interaction with the skin barrier, specifically within the <i>stratum corneum</i> (SC), which was studied by confocal microscopy. Results revealed that p(HPMA) can penetrate into deeper skin layers, with this ability inversely correlated with their molecular weight. FTIR analysis confirmed that the polymers increase SC hydration without disrupting lipid organization. As demonstrated by the <i>ex vivo</i> skin permeation study, the smallest p(HPMA) polymer (5 kg/mol) produced the strongest enhancement effect on IMQ delivery into skin tissue. Relative to p(HPMA)-free controls, IMQ accumulation increased by 90% from the conventional suspension and by 10% and 50% from the nanoemulsion and nanocrystal formulations, respectively. These findings substantiate the role of p(HPMA) as an effective skin-penetration enhancer and support its further investigation for optimizing topical drug-delivery systems.