A strong, silk protein-inspired tissue adhesive with an enhanced drug release mechanism for transdermal drug delivery

Abstract

In transdermal drug delivery system (TDDS) patches, achieving prolonged adhesion, high drug loading, and rapid drug release simultaneously presented a significant challenge. In this study, a PHT-SP-Cu²⁺ adhesive was synthesized using polyethylene glycol (PEG), hexamethylene diisocyanate (HDI), trimethylolpropane (TMP), and silk protein (SP) as functional monomers which were combined with Cu²⁺ to improve the adhesion, drug loading, and drug release of the patch. The structure of the adhesion chains and the formation of Cu²⁺-p-π conjugated network in PHT-SP-Cu²⁺ were characterized and elucidated using different characterization methods including FT-IR, ¹³C NMR, XPS, SEM imaging and thermodynamic evaluation. The formulation of pressure-sensitive adhesive (PSA) was optimized through comprehensive research on adhesion, mechanics, rheology, and surface energy. The formulation of 3 wt.% SP and 3 wt.% Cu²⁺ provided superior adhesion properties compared to commercial standards. Subsequently, the peel strength of PHT-SP-Cu²⁺ was 7.6 times higher than that of the commercially available adhesive DURO-TAK® 87–4098 in the porcine skin peel test. The adhesion test on human skin confirmed that PHT-SP-Cu²⁺ could adhere to the human body for more than six days. Moreover, the drug loading, in vitro release test and skin permeation test were investigated using ketoprofen as a model drug, and the results showed that PHT-SP-Cu²⁺ had the efficacy of improving drug compatibility, promoting drug release and enhancing skin permeation as a TDDS. Among them, the drug loading of PHT-SP-Cu²⁺ was increased by 6.25-fold compared with PHT, and in the in vivo pharmacokinetic analysis, the AUC was similarly increased by 19.22-fold. The mechanism of α-helix facilitated drug release was demonstrated by Flori-Hawkins interaction parameters, molecular dynamics simulations and FT-IR. Biosafety evaluations highlighted the superior skin cytocompatibility and safety of PHT-SP-Cu²⁺ for transdermal applications. These results would contribute to the development of TDDS patch adhesives with outstanding adhesion, drug loading and release efficiency.

Statement of significance

A new adhesive, PHT-SP-Cu²⁺, was created for transdermal drug delivery patches. Polyethylene glycol, hexamethylene diisocyanate, trimethylolpropane, silk protein, and Cu²⁺ were used in synthesis. Characterization techniques confirmed the structure and Cu²⁺-p-π conjugated networks. Optimal formulation included 3 wt.% SP and 3 wt.% Cu²⁺, exhibiting superior adhesion. PHT-SP-Cu²⁺ showed 7.6 times higher peel strength than DURO-TAK® 87–4098 on porcine skin and adhered to human skin for over six days. It demonstrated a 6.25-fold increase in drug loading compared to PHT, with 19.22-fold higher AUC in vivo studies. α-helix facilitated drug release, proven by various analyses. PHT-SP-Cu²⁺ showed excellent cytocompatibility and safety for transdermal applications. This study contributes to developing efficient TDDS patches.