Hydrogels represent a promising class of drug carriers for dermatological applications. They are characterized as specific, three-dimensional hydrophilic networks of polymers that maintain a stable structure despite high water content. Their favorable properties, such as plasticity, bio- and mucoadhesiveness, good washability, and similarity to natural tissues, make them highly suitable for use in medicine and pharmacy. Furthermore, the presence of water in hydrogels offers additional benefits for dermatological conditions, including cooling, moisturizing, pain relief, and support for wound healing. Sodium alginate (ALG), a natural, biocompatible, and biodegradable polysaccharide, is a particularly appealing polymer for hydrogel formulation. It can form gels through ionic cross-linking with divalent or trivalent metal cations, a process known as the “egg-box” model. While calcium chloride is commonly used, zinc ions (Zn2+) have garnered interest due to their enhanced interaction with alginate’s carboxyl groups, potentially leading to a more extensive and stable cross-linked network. Critically, Zn2+ ions also possess documented antifungal properties, making them advantageous for treating cutaneous mycoses. Another modification strategy for ALG involves combining it with cationic polymers, such as ε-poly-L-lysine (PLL), to form polyelectrolyte complexes (PECs) through electrostatic interactions. PLL is recognized as safe (GRAS) by the FDA and offers valuable properties including non-toxicity, biodegradability, and bacteriostatic and antifungal activity, which can further enhance the antifungal efficacy of the resulting hydrogels. Posaconazole (POS), a broad-spectrum triazole antifungal, is effective against various Candida species and dermatophytes. Despite its established efficacy, no topical formulations of POS are currently commercially available, highlighting a significant need for new delivery systems. The application of double cross-linking techniques has shown potential to improve the mechanical, rheological, and bioadhesive properties of hydrogels. Therefore, combining these strategies to develop dual-cross-linked alginate hydrogels loaded with posaconazole offers a compelling approach to enhance topical antifungal therapy.
Methods
This research focused on developing dual-cross-linked alginate hydrogels by employing two cross-linking techniques: ionic cross-linking with Zn2+ ions and electrostatic interaction with ε-poly-L-lysine (PLL). Initially, a 2% (w/w) sodium alginate (ALG) solution was prepared, to which a 0.1% (w/w) PLL solution was added dropwise, followed by dropwise addition of zinc acetate dihydrate (Zn(OAc)2·2H2O) at varying concentrations (optimal at 4%) under constant stirring to yield homogeneous dual-cross-linked hydrogels. Drug-loaded hydrogels were prepared by evenly distributing 1.0% w/w Posaconazole (POS) into the gel carriers. The study then comprehensively assessed the pharmaceutical properties of these hydrogels, including viscosity, rheology, texture, bioadhesiveness to hairless mice skin, and in vitro POS release. Furthermore, their antifungal activity against various Candida strains (C. albicans, C. krusei, and C. parapsilosis) was evaluated using agar diffusion, planktonic cell, and biofilm viability assays. Finally, the compatibility of the designed hydrogels with human fibroblasts was analyzed to ensure their safety for dermatological application.
Key Findings
The study yielded several significant findings regarding the dual-cross-linked alginate hydrogels:
• Improved Pharmaceutical Properties: The double cross-linking process significantly increased the viscosity of the developed ALG hydrogels. The formulations were homogeneous, lacked phase separation, and exhibited even dispersion of posaconazole (POS) particles with acceptable drug content. The pH values of the hydrogels (5.04–6.20) were found to be compatible with the skin surface, minimizing irritation risk.
• Enhanced Bioadhesion: Dual cross-linking improved the bioadhesive properties of the hydrogels to hairless mice skin, as evidenced by higher detachment force (Fmax) and work of adhesion (Wad). The presence of POS further increased Fmax and Wad values. The intrinsic bioadhesive properties of ALG, PLL, and Zn2+ all contributed to this effect.
• Extended Drug Release Profile: The double cross-linking process provided an extended release profile of POS from the hydrogels. This prolongation was closely associated with the increased viscosity and denser hydrogel matrix of the dual-cross-linked formulations, which limited drug diffusion.
• Optimal Rheological and Textural Characteristics: All formulations exhibited shear-thinning fluid behavior, which is beneficial for application. Dual-cross-linked formulations demonstrated statistically significant improvements in firmness, consistency, and cohesiveness, indicating a more robust structure.
• Increased Antifungal Efficacy: The obtained formulations were characterized by an improved antifungal effect against C. albicans, C. krusei, and C. parapsilosis. Dual-cross-linked formulations (both placebo and POS-containing) generally showed higher antifungal activity. Notably, the formulation with Zn2+ (F3) possessed the most pronounced potential for inhibiting Candida biofilm formation. The inherent antifungal properties of the hydrogel matrix constituents—ALG, PLL, and Zn2+ ions—contributed significantly to the overall antimycotic action.
• High Biocompatibility: The prepared hydrogels expressed biocompatibility with human fibroblasts. All tested formulations preserved the morphology of human skin fibroblasts and showed no significant alterations in cell number for up to 24 hours, meeting pharmaceutical product viability standards established by the FDA and ISO.
• Structural Compatibility and Thermal Stability: Thermal analysis and FTIR spectroscopy confirmed good compatibility between POS and the excipients, indicating the successful formation of polyelectrolyte complexes and coordination bonds within the dual-cross-linked structure. The dual-cross-linked hydrogels also possessed notable thermal stability.
The future implications of this research are substantial. Dual-cross-linked alginate hydrogels represent a promising dermatological formulation that could revolutionize the efficacy of posaconazole in treating persistent and recurrent antifungal infections. Their sustained drug release and enhanced bioadhesive properties suggest the potential for prolonged drug retention on the skin, which could lead to improved therapeutic outcomes and better patient adherence by maintaining a consistent therapeutic concentration at the site of application. This innovative approach offers a robust platform for developing new topical treatments for chronic dermatological fungal infections, including those caused by drug-resistant pathogens, thus addressing a significant unmet medical need.
Link to the study: https://www.mdpi.com/1999-4923/17/8/1055
